PBL 46 Flashcards
What are the 2 main sub-types of lung cancer?
- NSCLC
2. SCLC
What is the most common subtype of lung carcinoma?
Non-small cell lung carcinoma (87%) of which the majority are adenocarcinomas (40%)
What are the main causes of lung cancer?
- Smoking (90%)
- Occupational exposure to carcinogens such as radon, arsenic, asbestos, chromates, nickel (9-15%)
- Environmental radon (10%)
- Outdoor and indoor air pollution (1-2%)
- Underlying chronic lung disease
- FHx
Adenocarcinoma common driver mutations
- EGFR
- ALK
- KRAS
Which of the adenocarcinoma common driver mutations is most commonly seen in smokers and which is more common in non-smokers?
Smokers - KRAS mutation
Non-smokers - EGFR mutation
Non-small cell lung carcinomas are all associated with which lifestyle activity?
Smoking
What are the most common types of NSCLC?
- Adenocarcinoma (40%)
- Squamous cell carcinoma (20%)
- Large cell carcinoma (2%)
Squamous cell carcinoma has more mutations per megabase than other common cancers, true or false?
TRUE
What is the most frequent gene mutation in squamous cell carcinoma?
TP53 (encodes P53 protein)
Which of the subtypes of lung carcinoma is has the worst prognosis?
Small cell lung carcinoma (SCLC)
What are the common driver mutations for small cell carcinoma?
TP53 and RB1 - inactivated in 100% of tumours!
Mutation of which gene is said to be a hallmark of SCLC?
RB1
Explain the pathogenesis of squamous cell carcinoma?
- Normal respiratory epithelium - pseudostratified columnar ciliated epithelium
- Squamous metaplasia - adaptive process caused by irritation to bronchial epithelium (smoking etc), now you have squamous cell epithelium replacing the pseudostratified columnar ciliated (bronchial) epithelium because it is more resistant to these irritants
- Squamous dysplasia - since the squamous epithelium is not meant to be in this area, it goes through unregulated mutations and eventually dysplasia occurs. This is disordered cell growth which is seen by a loss of normal architecture and of uniformity of individual cells. PRECEDES BUT DOES NOT INVARIABLY LEAD TO CANCER
- Malignancy - Excessive growth of abnormal squamous cells. Locally invasive. Able to form metastases via lymphatics and blood vessels
Explain the pathogenesis of adenocarcinoma
- Pneumocytes lining epithelia begin changing from squamous cells to cuboidal cells, this is atypical alveolar cell hyperplasia = precursor lesion
- Eventually the tumour becomes invasive and infiltrates normal tissue
Common symptoms of lung carcinoma
- Cough (75%)
- Weight loss (40%) ADVANCED SIGN
- Chest pain (40%) ADVANCED SIGN
- Dyspnoea (20%)
Local effects of a lung carcinoma (in the lungs) - explain how for each one
- Pneumonia/abscess/lobar collapse - Tumour airway obstruction may cause tissue distal to the obstruction to become infected
- Lipid pneumonia - Secretions accumulate distal to the blockage (including lipid rich surfactant) can cause lipid pneumonia as airspaces are filled up with cells so no gas exchange
- Pleural effusion - Tumour spread to the pleura
- Hoarseness - Tumour invades the recurrent laryngeal nerve
Local effects of a lung carcinoma (extra to the lungs) - explain why for each
- Dysphagia - oesophageal invasion by tumour
- Diaphragm paralysis - phrenic nerve invasion by tumour
- Rib destruction - chest wall invasion by tumour
- SVC syndrome - SVC compression by tumour
- Horner syndrome - Sympathetic ganglia invasion by tumour at apex lung (Pancoast tumour)
- Pericarditis - pericardial involvement
- Pancoast tumour - brachial plexus invasion leads to hand muscle weakness and axillar & shoulder pain
What is Horner syndrome? S&S?
Combination of signs and symptoms caused by disruption of sympathetic ganglia which innervated the face and eye on one side of the body
S&S:
- Constricted pupil (miosis)
- Drooping of upper eyelid (ptosis)
- Absence of face sweating (anhidrosis)
SVC compression occurs particularly with tumours that spread to which lymph nodes?
Mediastinal lymph nodes
Systemic effects of lung carcinoma
- Metastatic spread: bone, brain, liver, skin, adrenal glands
- Paraneoplastic syndromes (S&S due to a tumour) secondary to ectopic production of hormones by the lung cancer cells
- Lambert-Eaton myaethnic syndrome - auto-antibodies against neuronal calcium channels
- Peripheral neuropathy
- Dermatological abnormalities
- Haematological abnormalities
- Hypertrophic pulmonary osteoarthropathy with clubbing
Examples of paraneoplastic syndromes secondary to ectopic production of hormones by the lung cancer cells
- ADH - hyponatraemia (commonly in SCLC)
- ACTH - Cushing syndrome
- Parahormone - hypercalcaemia (commonly in squamous cell carcinoma)
- Calcitonin - hypocalcaemia
- Gonadotrophins - gynaecomastia
- Serotonin and bradykinin - carcinoid syndrome
Treatment for lung cancer
- Surgery
- Radiation therapy
- Chemotherapy
- Targeted therapy
Main treatment for NSCLC that has not spread beyond the lung?
Surgery
When may surgery for NSCLC not be possible?
When it has spread beyond the lungs
When it is too close to the trachea
If the person has other serious conditions (severe heart or lung disease)
Main treatment for SCLC?
Chemotherapy and radiation therapy in combination (AGGRESSIVE!)
Why is surgery not used for SCLC even in early stages?
Due to its aggressive nature, this requires chemo or radiation therapy
Which lung cancer subtypes is radiation used for? Why?
Both NSCLC and SCLC
- It is for those who cannot undergo surgery for other reasons (such as coronary artery disease) or those whose cancer has metastasised to nearby lymph nodes
For which lung cancer subtypes is chemotherapy used?
Both NSCLC and SCLC
Main treatment for NSCLC which is advanced and has spread beyond the lungs?
Palliative chemotherapy and/or radiotherapy
Drug treatments for lung carcinoma
- Molecular targeted drugs for adenocarcinoma
2. Platinum based drugs
Molecular targeted drugs in adenocarcinoma (NSCLC) N.B EGFR and ALK mutations
- EGFR mutation = tyrosine kinase inhibitors such as eriotinib and gefitinib
- ALK gene rearrangement = ALK inhibitors such as crizotinib
Examples of platinum based drugs used for lung cancer treatment? MoA and side effects?
Cisplatin and carboplatin
MoA: Cause cross-linking of DNA which inhibits DNA repair and/or synthesis in cancer cells
Side effects: neurotoxicity, causing peripheral neuropathies including POLYNEUROPATHY
Use and MoA of paclitaxel
Used for NSCLC in patients unsuitable for curative treatment
MoA: ANTI-MICROTUBULE agent: inhibits spindle function by preventing disassembly, so it blocks mitosis and activates the mitotic checkpoint to trigger apoptosis or reversion of the G-phase of the cell cycle without division occuring!
What is bronchitis?
Inflammation of the bronchi
Signs and symptoms of bronchitis?
- Coughing
- Sputum production
- Fever
- Sore throat
Pathogenesis of acute bronchitis
- Respiratory tract infection (RTI) triggers acute inflammation of the bronchi
- Bronchial-lining tissue cells are irritated and the mucous membrane becomes HYPEREMIC and EDEMATOUS, diminishing bronchial mucociliary function
- Consequently, the air passages become clogged by debris and irritation increases
- In response, copious secretion of mucus develop, which causes the characteristic bronchitis cough
- In most people, the viral infection clears within a few days, but repair of the bronchial wall takes much longer, so patients often cough for several weeks after (post-bronchitis syndrome)
Bronchitis is more commonly bacteria-caused, true or false?
False
- It is usually viral
Most common viruses causing acute bronchitis?
- Rhinovirus
- Adenovirus
- Influenza A and B
- Parainfluenza virus
What is chronic bronchitis?
Long term exposure to irritants resulting in permanent damage to the airways (e.g smoking)
Pathogenesis of chronic bronchitis?
- Continuing irritation causes ongoing inflammation of the airway walls, which leads to structural changes, including hyperplasia and hypertrophy of cells and mucus glands, accompanied by fibrosis and consequential thickening of the airway walls
- Sustained exposure leads to progression of the disease accompanied by further squamous metaplasia and fibrosis, which, combined with excessive mucus production, leads to even greater restriction of airflow
Breaking bad news acronyms?
SPIKES
ABCDE: A = advanced preparation B = building a relationship C = communicate well D = deal with patient reactions E = encourage and validate emotions
TB is caused by which pathogen?
Mycobacterium Tuberculosis
A single aerosol inoculation is required for TB infection, true or false?
False
- Multiple aerosol inocula are required
What are the different sites involved in TB?
Pulmonary
Extrapulmonary - lymph node, genito-urinary tract, bones and joints, meninges, intestine, skin
TB presents as either…
Primary TB
Secondary TB
What is primary TB?
First exposure, can be progressive or latent
What is secondary TB?
Dormant or reinfection
The progression to clinical disease in a previously unexposed, immunocompetent person depends on which 3 factors:
- Infective dose and virulence
- Development of anti-mycobacterial cell-mediated (CD4) immunity
- The number of M. tuberculosis organisms inhaled
Explain the pathogenesis of primary TB infection
- Inhaled, droplet nuclei are deposited within the alveoli of lower part of upper or lower lobe
- M. tuberculosis enters the macrophages by endocytosis
- Inside the macrophage, M.tuberculosis replicates within the phagosome by blocking phagolysosome formation (inhibition of Ca2+ signals & blocking recruitment and assembly of proteins which mediate fusion)
- Some macrophages migrate to lymph nodes and take the bacterium with it, causing the infection to spread
- Small area of grey white inflammation with consolidation develops (granuloma/tuberculoma) inside has caseous necrosis which looks like cheese. Together these make up the Gohn focus, and all Gohn focuses make up the Gohn complex
- Hypersensitivity reaction is strong in mycobacterial infections because of potent adjuvant activity of mycobacterial lipids
- After 3 weeks, Th1 response against M. tuberculosis, activated macrophages become bactericidal
- Th1 cells have T cell receptors capable of recognising mycobacterial antigens presented by macrophages
- Differentiation of Th1 depends on IL-12 produced by APCs
- Mature Th1 cells produce IFN-gamma which drives macrophages to become competent
- Activated macrophages accumulate high concentrations of lytic enzymes and reactive metabolites that greatly increase their mycobactericidal competence
- After some time there are three possible outcomes:
A) Dead - killed by macrophages
B) Dormant - bacteria inside macrophages
C) Multiplying
What is primary progressive infection due to TB? Who is it more common in?
It is when people go on to develop a problem shortly after that have been infected with TB
- More common in children, it leads to tuberculosis pneumonia
What is secondary TB? Where does it usually form?
Reactivation of previous latent infection (or reinfection).
- Secondary TB forms a cavity, particularly in the upper lobes rather than the lower lobes in primary progressive TB
Risk factors for TB
- Long term care facilities: prisons, shelters
- Extreme poverty
- Having HIV
Risk factors for TB reactivation
- HIV
- Diabetes
- Long term corticosteroid use
- Anti-inflammatory drugs: Inflixumab
- Head and neck cancer
- Surgery to remove or all part of the stomach
- Chronic kidney problems
- Tobacco use
- Substantial weight loss
Signs and symptoms of TB
- Fever
- Night sweats
- Coughing
- Haemoptysis
- Fatigue
- Weight loss
Treatments for TB? RIPE
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Combination therapy for TB?
Rifampicin and isoniazid given for 6 months and pyrazinamide and ethambutol for the first 2 months of the 6 month period
Drug resistant TB can occur when…
- Not completing full course of TB treatment
- Health care provider prescribing the wrong treatment
- Drugs for proper treatment are not available
- Drugs are of poor quality
Drug-resistant TB is more common in people who…
- Do not take their TB drugs regularly
- Do not take all of their TB drugs
- Develop TB again after being treated for TB in the past
- Can’t absorb the drugs properly
- Come from areas where drug-resistant TB is common
- Have spent time with someone with drug-resistant TB
Types of drug resistant TB, what are each resistant to?
- Multidrug-resistant TB: isoniazid and rifampicin
2. Extensively drug-resistant TB (XDR TB): RIPE & fluoroquinolone & second-line drugs
TB is now concentrated in certain medically undeserved populations…
- Urban poor
- Alcoholics
- IV drug users
- Homeless
- Prison inmates
