Lung Cancer + Basic Sciences Flashcards
Risk factors for lung cancer
• Smoking
○ Increases risk of lung ca by a factor of 10
○ Weaker association with lung adenocarcinoma
• Other factors
○ asbestos - increases risk of lung ca by a factor of 5
§ Smoking and asbestos are synergistic, i.e. a smoker with asbestos exposure has a 10 * 5 = 50 times increased risk
○ arsenic
○ Radon - 2nd leading cause of lung cancer
○ nickel
○ chromate
○ aromatic hydrocarbon
○ cryptogenic fibrosing alveolitis
• Factors that are NOT related
○ coal dust
• Family history (genetic predisposition)
• Other RF: pulmonary scarring, previous radiation, pulmonary fibrosis, chronic infections (eg: TB, HIV)
What is the most potent carcinogen in cigarette smoke?
Polycyclic aromatic hydrocarbons
Types of lung cancers
Lung cancer is divided into 2 types:
(1) Small Cell Lung Cancer 13%: central location, rapid tumour growth, early metastases and associated with numerous paraneoplastic syndromes
(2) Non-Small Cell Lung Cancer
- Adenocarcinoma (peripheral) - most common 40% and more common in women + non smokers
- Squamous cell carcinoma (central) 20%
- Large cell carcinoma 7%
Features of adenocarcinoma
- Location
- Characteristics
- Peripheral
- Most common form of lung cancer
- More common in women and non-smokers
- Associated with mutations in EGFR/ALK/KRAS gene
- Risks with pulmonary fibrosis
- Prognosis usually better than other lung cancer
- Gynaecomastia due to production of HCG (increased risk with large cell carcinoma + poorly differentiated adenocarcinoma)
- Increased risk with adenocarcinoma: thrombophlebitis migrans, nonbacterial verrucous endocarditis
Features of squamous cell carcinoma
- Location
- Characteristics
- Location: central “sentrally located”
- Strong associations with smoking
- Cavitations
- Cavitary lesions arising from hilar bronchus
- PThrP: hypercalcemia
- Histology: Intercellular bridges (desmosomes)
Keratin pearls
C; central location, hypercalcemia, cavitations
Features of large cell carcinoma
- Location
- Characteristics
- Location: peripheral
- Poor response to chemotherapy
- Early mets
- Poor prognosis
Features of small cell lung cancer
- Location
- Features
- Location: central
- Strong association with SMOKING-almost all cases are in smokers
- Very CHEMOTHERAPY SENSITIVE
- Associated with several PARANEOPLASTIC syndromes
• Cushing syndrome
• SIADH
• Lambert Eaton Syndrome: ab against voltage gated calcium channels - Undifferentiated and very aggressive with early metastases
- Associated mutations: L-myc oncogene
- Classically bulky lymphadenopathy
- Chemo+ radiosensitive
- Doesn’t cause clubbing
- CNS METS FREQUENT - MRI BRAIN
Staging of SCLC
Only 2 stages: limited and extensive
Limited: disease in one haemothorax and ipsilateral mediastinal nodes, encompassable by a single radiation field
Extensive: anything that’s not limited
Treatment for SCLC
LIMITED
- Curable (20-30%) with concurrent chemoradiation (CISPLATIN + ETOPOSIDE) and PCI (prophylactic cranial irradiation) in responders as brain is a brain sanctuary site for micromets
EXTENSIVE
- Generally incurable
- BUT expect excellent response with chemo/RT even in very unwell patients
- Median survival 12 months with chemoimmunotherapy
Chemotherapy (CARBOPLATIN + ETOPOSIDE) + ATEZOLIZUMAB (PDL1 inhibitor) improved PFS + OS
Features of mesothelioma
- Asbestos and tobacco related 10-20x risk of mesothelioma Asbestos risk of NSCLC - especially squamous cell carcinoma - Long latency (30-40 years) - Usually pleural or peritoneal
Epitheloid more common but sarcomatoid has worse survival
Tx:
- Generally incurable, role of surgery + radio is limited
- Radical Tx: extrapleural pneumonectomy
- Palliative chemo improves survival: cisplatin + pemetrexed
Nivolumab + ipilimumab in unresectable malignant pleural mesothelioma
Pancoast tumour
• Apical lung carcinoma
• Superior sulcus tumour
• Predominantly NSCLC
• May lead to the development of Pancoast Syndrome: constellation of symptoms secondary to the mass effect of the tumour on surrounding structures
○ Cervical sympathetic ganglion (stellate ganglion): Horner syndrome (ipsilateral miosis - small pupil), ptosis, anhidrosis)
○ Brachial Plexus: localised pain in the axilla and shoulder (plexus neuralgia)
- Upper limb motor and sensory deficits (eg: hand muscle weakness and atrophy) - wasting hand muscles (T1)
○ Recurrent laryngeal nerve: hoarseness
○ Brachiocephalic vein
- Unilateral oedema of the arm
- Facial swelling
○ Phrenic Nerve: paralysis of the hemidiaphragm (visible as elevated hemidiaphragm on CX
NOTE:
The right and left recurrent laryngeal nerves are not symmetrical, with the left nerve looping under the aortic arch, and the right nerve looping under the right subclavian artery then traveling upwards.
What are the common sites of metastsis for lung cancer?
Lung cancer loves to BLAB
- Brain
- Liver
- Adrenals
- Bone
Paraneoplastic syndromes of lung cancer
Shared paraneoplastic features
- Cachexia
- Thrombocytosis + DIC
- Hypercoagulability
- Dermatomyositis
- Acanthosis negricans
NSCLC
- Hypercalcaemia of malignancy - increased risk with squamous cell
- Gynaecomastia due to production of HCG (increased risk with large cell carcinoma + poorly differentiated adenocarcinoma)
- Hypertrophic osteoarthropathy
- Increased risk with adenocarinoma: thrombophlebitis migrans, nonbacterial verrucous endocarditis
SCLC
- Cushing syndrome
- SIADH
- Lambert eaton syndrome
- Paraneoplastic cerebellar degeneration
- Peripheral neuropathy
Clinical features of lung cancer
• Pulmonary Symptoms:
- Cough, haemoptysis
- Progressive dyspnoea
- Wheezing
- Chest pain
• Extrapulmonary Symptoms
- Constitutional symptoms - weight loss, fever, weakness
- Signs and symptoms of tumour infiltration and/or compression of neighbouring structures
SVC syndrome: impairs venous backflow to the right atrium, resulting in venous congestion in the head, neck and upper extremities
Treat with steroids
Common in SCLC
Hoarseness: paralysis of the recurrent laryngeal nerve
Dyspnoea and diaphragmatic elevation: paralysis of the phrenic nerve
Dullness on percussion + reduced breath sounds: malignant pleural effusion on the affected side
Dysphagia: oesophageal compression
What should you be concerned about if a patient >40yo has recurrent respiratory infections (eg: pneumonia ) in the same pulmonary region?
Lung cancer
Investigation for lung nodule
- <5mm: no follow up if malignancy risk is low
If high to consider serial CT scans - 5-7mm: Serial CT scans
- > 8mm: PET or biopsy
If suspicious for malignancy - resection!
Diagnosis for lung cancer
- Central endobronchial lesions: bronchoscopy
- Peripheral lung lesions: radiology guided core biopsies
- Central nodes: EBUS (endobronchial US)
Diagnosis: morphology + immunohistochemistry/molecular testing
- TTF-1 and Napsin A +ve for adenocarcinoma (TANA)
- Non squamous NSCLC (adenocarcinoma/large cell): EGFR, ALK, ROS1
- PDL1 expression for all NSCLC (squamous, adeno, large cell)
Imaging for lung cancer
- If CXR raises suspicion –> CT scan
- PET to stage mediastinum and identify metastatic disease if curative intent is planned for NSCLC
- Isolated PET positive findings require histological confirmation
- PET not sensitive for brain - requires ideally MRI Brain
Staging for NSCLC and basic treatment
Stage 1: No nodal involvement
- Surgical resection if medically fit - lobectomy vs pneumonectomy
Lobectomy with mediastinal LN dissection is recommended for tumours >2cm
- Stereotactic radiation if non surgical candidate
Stage 2 A+B: Ipsilateral peribronchial and/or hilar LN and intrapulmonary nodes
- Surgical resection + adjuvant chemo
Stage 3A: ipsilateral mediastinal and/or subcarinal LN
Stage 3B: contralateral mediastinal, hilar, supraclavicular LN
- Resectable: neoadjuvant chemo + surgical resection
- Unresectable: concurrent chemoradiation and DURVALUMAB (PDL1) for 12 months
Stage 4: metastatic disease including malignant pleural effusion + contralateral lung nodules
- Palliative systemic therapy - chemotherapy, targeted therapy and immunotherapy
+ palliative RT
Adjuvant Chemo
- Consider for all fit stage II-III patients post resection
- No conclusive benefit for stage IV
- Generally 4 months of cisplastin + venorelbine
What are the driver mutations in non squamous cell carcinoma (adenocarcinoma, large cell)?
Who should be tested?
Driver Mutations in NSCLC - EGFR - ALK - ROS (EAR)
Who should be tested?
- All lung ADENOCARCINOMAS
- All carcinomas with a component of adenocarcinoma, eg: adenosquamous carcinoma
- Large cell carcinoma
- Never smokers with squamous cell carcinoma
Driver mutations are absent or extremely rare in
- Pure squamous cell carcinoma
- Classic small cell lung cancer
- Large neuroendocrine carcinoma
Stage IV targeted therapies for lung cancer
Factors to Consider
- Presence of driver mutations: EGFR, ALK rearrangements, ROS 1
- Presence of PDL-1
- Squamous vs Non squamous (squamous more aggressive and no therapy available)
- ECOG
- RT for palliation + brain mets
EGFR TKIs
- Erlotinib
- Gefitinib
- Afatinib
- Osimertinib for T790M +ve
ALK TKIs
- Crizotinib
- Alectinib
ROS 1 TKI
- Crizotinib,
- Entrectinib
EGFR mutations
Osimertinib - 1st line - For T790M +ve patients - 3rd gen - Wouldn't give if non exon 19/L85*R Gefitinib, Erlotinib - 1st gen Afatinib - 2nd gen
- Most common EGFR activating mutations
Exon 19 deletion
Exon 21 point mutation L858R
More common in :
- Non smokers
- Females
- Asian ethnicity
- Adenocarcinoma
For patients with EGFR mutation, more effective than chemo
Side effects of EGFR inhibitors
Osimertinib, Gefitinib, Afatinib
- Acneform rash - presence of rash is correlated with response to therapy. Treat with topical or oral abx (tetracyclines), topical steroids, skin care, sun protection - Diarrhoea - Macular oedema - Alopecia - Nail changes - Pulmonary toxicity Don't cause cytopenia
EGFR inhibitor resistance
- Progression due to resistance common after 6-24 months
- 60% due to T790M resistance mutation
- Osimertinib (3rd gen EGFR TKI) highly active
