Respiratory JC018: Pleural Effusion In A Chronic Smoker: Pleural Effusion, Lung Cancer Flashcards
Case: 64 yo male, chronic smoker, retired restaurant worker
- Pleural effusion on CXR
—> Diagnostic + Therapeutic tapping x2
—> Exudative changes
—> Atypical cells with large N/C ratio (need to rule out malignancy)
—> but Pleural fluid cytology + Percutaneous biopsy non-diagnostic
Pathophysiology of pleural effusion
Pleural space: between parietal + visceral pleura
Imbalance across membranes —> movement of fluid from vascular space to pleural space —> accumulation
Parietal pleura (Arterial capillary) + Visceral pleura (Venous capillary):
1. Hydrostatic pressure (push fluid into pleura)
2. Oncotic pressure (draw fluid)
3. Lymphatic drainage (draw fluid)
4. Capillary permeability (leakage of fluid into pleural cavity)
Hydrostatic pressure
↑ due to abnormal fluid retention:
1. **Congestive HF
2. **Renal failure
3. Other forms of volume overload
Oncotic pressure
↓ mainly due to ↓ plasma protein (esp. Albumin):
1. **Cirrhosis
2. **Nephrotic syndrome
3. Severe malnutrition
4. ***Other forms of hypoalbuminemia
Capillary permeability
↑ due to **pleural inflammation:
1. **Infection of lung / pleura (including TB)
2. Collagen vascular disease (involving pleura)
3. **Malignant involvement of pleura
4. Intra-abdominal process (e.g. **pancreatitis, ***liver abscess)
Lymphatic drainage
↓ due to:
1. ***Malignant infiltration of mediastinal, pulmonary, pleural lymphatics
—> ↑ pressure in downstream lymphatics
- Necrotising / ***Granulomatous infections
***Transudative vs Exudative fluid
Transudative:
1. ↑ Hydrostatic pressure
2. ↓ Oncotic pressure
—> ***Pure water movement
Exudative:
1. ↑ Capillary permeability
2. ↓ Lymphatic drainage
—> Direct leakage
—> ***Protein movement also
***Investigations of Transudative vs Exudative fluid
Diagnostic thoracentesis (aka pleural tapping) + ***Pleural fluid analysis
記: ABCCM
- ***Appearance
- turbid
- blood stained
- clear / straw colour - Biochemistry
- ***Protein + LDH (Light’s criteria)
- Glucose, pH - ***Cell count + differential
- Empyema: Neutrophil predominant
- Tuberculous pleurisy: Lymphocyte predominant - ***Cytology
- malignancy / atypical cells
(- 70% yield (CL Lai)) - ***Microbiology
- smear for AFB / other bacteria
***Light’s criteria
Exudative effusion, ***>=1 of following:
- Pleural fluid protein / Serum protein > 0.5
- Pleural fluid LDH / Serum LDH > 0.6
- Pleural fluid LDH > 2/3 normal upper limit for serum
Glucose, pH:
- ↓ together in some exudative process e.g. empyema, rheumatoid pleurisy
Other investigations
- Percutaneous pleural biopsy
- ***exudative effusion
- esp. to confirm TB / cancer - Thoracoscopy / ***Pleuroscopy
Aim: Identification of primary cause of pleural fluid formation
Lung cancer epidemiology
Male patients:
- Predominant
- 80% smokers
Female patients:
- <40% smokers
- >75% **Adenocarcinoma
- high prevalence compared to other countries
—> Environmental factors: Passive smoking, diet, cooking fumes
—> Genetic factors: **EGFR gene mutation important in some non-smoking patients with adenocarcinoma
Pathogenesis of Adenocarcinoma and SCC
Heterogeneous
SCC: arise from ***Central compartment (Bronchial structures)
- Series of transition: Normal epithelium —> Metaplasia —> Dysplasia —> CIS —> SCC
Adenocarcinoma: **Peripheral compartment (Bronchiolo-alveolar structures)
- Not very known
- **Variable histology (can be ∵ heterogeneous genetics abnormalities)
- Normal alveolar / Bronchiolar epithelium
—(less known changes)—> ***Atypical adenomatous hyperplasia (AAH)
—> Invasive Adenocarcinoma
***WHO classification of lung tumour histology
Epithelial tumours:
1. Non-small cell lung cancer (85%)
- Adenocarcinoma (45-55%)
- SCC (20-30%)
- Large cell carcinoma (5-10%)
- Small cell lung cancer (5-10%)
- Mixed
Mesothelial tumours:
1. Malignant mesothelioma
Miscellaneous malignant tumours
***Clinical presentation of lung cancer
Very variable:
- **Patch of consolidation / **Lung mass / **Diffuse involvement / **Pleural effusion
Identification of patients based on:
- Clinical S/S
- Clinical syndrome
- Incidental findings on asymptomatic individuals
- Identification of at risk population
***S/S of lung cancer
- Radiological abnormality only
- ***Constitutional symptoms
- malaise
- ↓ appetite
- ↓ body weight - Primary lesion
- Bronchial mucosa ulceration
—> cough, sputum, ***haemoptysis
-
**Obstructive
—> partial: **wheeze, unresolved pneumonia, dyspnea
—> complete: ***lung collapse
- Intrathoracic spread
- Along lymphatics to both lungs —> **Lymphangitis carcinomatosis: cough, dyspnea (Diffusely opacified both lung fields, DDx: Miliary TB (SpC Medicine))
- **Pleura —> Pleural effusion: chest pain, dyspnea
- **Pericardial effusion —> Cardiac tamponade: dyspnea
- **SVC obstruction: dyspnea, stridor, dysphagia, face swelling
- **L Recurrent laryngeal nerve (L>R ∵ longer course (self notes)): hoarseness
- **Brachial plexus (C8-T2) —> **Pancoast’s syndrome (Davidson): pain in shoulder / arm
- **Inferior cervical sympathetic ganglion —> **Horner: loss of sweating on 1 side of face
- **Esophagus: dysphagia
- ***Chest wall, Ribs: chest pain, swelling - Extra-thoracic manifestations
- Cachexia
- Clubbing
- Supraventricular LN + cervical LN enlargement
- **Liver: hepatomegaly, deranged LFT
- Brain: seizures, change in personality, vomiting
- **Bone: pathological fractures, hypercalcaemia, bone pain
- Adrenal: cortisol insufficiency (rarely)
- ***Spinal cord: cord compression
- Skin
- Choroidal: impaired VA
- Unexplained anaemia - Paraneoplastic syndrome (Systemic non-metastatic syndrome)
- CT
—> **Clubbing, **Hypertrophic pulmonary osteoarthropathy (HPOA): arthralgia, pain, tenderness of extremities
- Ectopic hormones
—> ADH (↓ Na) (e.g. **SIADH) (SCLC (Davidson)): weakness, confusion
—> *ACTH (↓ K) (SCLC (Davidson)): weakness
—> Parathyroid Like-peptide (PLP) (↑ Ca): polyuria, thirst, confusion - Neuromuscular
—> Encephalopathy: dementia, confusion
—> **Cerebellar degeneration: ataxia, clumsiness
—> **Peripheral neuropathy: paresthesia, weakness
—> Myasthenia-like (Lambert-Eaton (SCLC (web)))
—> ***Dermatomyositis (rmb to rule out other head/neck cancer)
***Investigations of lung cancer
Aim:
1. Differentiate benign vs malignant
(2. Assess Primary vs Secondary tumour (self notes))
3. Confirm diagnosis + histological subtypes
4. Stage tumour
5. Assess fitness of patient
—> Select treatment modality
Investigations:
1. CXR
- Cytology
- **sputum
- **bronchial washing + brushing
- pleural fluid
- fine needle aspiration - Histology (better classify subtype + molecular genetic testing)
- **bronchoscopic biopsy: bronchial / transbronchial
- pleura
- LN
- metastatic sites
- **exploratory thoracotomy - Staging and Surgical assessment of lung cancer
- imaging +/- invasive procedures e.g. bronchoscopy, percutaneous sampling
- lung function assessment
- cardiac assessment
- blood tests: LFT, RFT, Ca
- ***PET-CT
PET-CT
- Exclude extrathoracic involvement
- Assess extent, activity, size of tumour
—> anatomical size
—> invasion into adjacent structures - Excellent tumour imaging
- FDG taken up by cells in glycolysis
—> bound within these cells
—> cannot enter normal glycolytic pathway - ↑ activity in cells with high metabolic rates (e.g. tumours, areas of inflammation)
***Other Pulmonary interventions (besides bronchoscopy)
Mediastinal LN:
1. CP-EBUS-TBNA (Convex probe-Endobronchial ultrasound-Transbronchial needle aspiration)
—> can see Station 4, 7, 10, 11 mediastinal LN
Tumours in peripheral thorax:
1. Radial probe-EBUS
2. Navigational bronchoscopy
3. **Image-guided **percutaneous biopsy
Pleural lesions:
1. ***Pleuroscopy / Indwelling pleural catheter
- semi-rigid instrument ~ percutaneous chest drain
- direct visualisation of pleura + sampling
Others:
1. Autofluorescence imaging
Endobronchial ultrasound (EBUS)
- Ultrasound probe at tip of bronchoscope
- Assess subcarinal, upper, lower paratracheal, hilar LN —> for subsequent aspiration
- 90% sensitivity
- 20% false negative
CP-EBUS-TBNA indications:
1. Staging: Sampling of mediastinal LN (station 4, 7, 10, 11)
- Alternative diagnosis for ***mediastinal lymphadenopathy
—> TB, sarcoidosis, lymphoma - ***Tumour mass immediately adjacent to accessible part of airway through EBUS bronchoscope
Staging for Non-small cell lung cancer
TNM staging:
T: Tumour size + local invasion
N: LN: hilar, mediastinal, extra-thoracic, ipsilateral vs contralateral
M: Metastasis
Stage 1: early disease (resectable)
Stage 2: early disease (resectable)
Stage 3: **locally advanced disease (may need **chemotherapy / ***radiotherapy before resectable)
Stage 4: advanced / metastatic disease (systemic / palliative treatment)
***Treatment for lung cancer
Non-small cell lung cancer:
- Early stage: ***Resection —> Relapse —> Chemo / Targeted / Immuno
- Locally advanced: ***Tests for targets —> Chemo / Radio / Resection —> Tests for targets —> Chemo / Targeted / Immuno
- Advanced: ***Chemo —> Chemo / Targeted / Immuno
Small cell lung cancer:
- Limited stage: Chemo / Radio
- Extensive stage: Chemo / Radio
***Chemotherapy
Indication:
- ***Advanced stage NSCLC with no actionable mutation
Cyclical combination chemotherapy:
**Platinum drug (Cisplatin / Carboplatin) + **Cytotoxic drug (Pemetrexed, Taxol, Gemcitabine)
—> SCC: Pemetrexed not recommended
Response rate: 30-40%
SE: Myelosuppression
Differentiate histology type: Adenocarcinoma
Endobronchial biopsy + Immunohistochemistry staining
Adenocarcinoma:
- **CK7 positive —> signify pulmonary epithelial origin
- **TTF1 positive —> signify pulmonary epithelial origin
- CK20 negative (i.e. not from gut origin where adenocarcinoma can still occur)
Mutations of Adenocarcinoma
Asians:
- ***EGFR (55%)
- KRAS (5-10%)
Caucasians:
- KRAS (30%)
- EGFR (10-15%)
***Molecular targeted therapy
Indications:
- Tumour with **Oncogenic **molecular targets
Targeted therapies in NSCLC:
1. Sensitising EGFR mutations at exons 18-21 (e.g. Exon 19 deletion, L858R, L861Q)
- ***Gefitinib
- Erlotinib
- Afatinib
- Resistant EGFR T790M mutation
- ***Osimertinib - EML4-ALK gene rearrangement
- ***Crizotinib
- Ceritinib
- Alectinib - ROS1 gene rearrangement
- Crizotinib
***EGFR Tyrosine Kinase Inhibitors (TKI)
EGFR mutations: Heterogeneous
Mutations detectable in tumours / plasma DNA
Deletion in Exon 19, L858R, L861Q in Exon 21
- more drug sensitive to 1st gen TKI
—> ***Gefitinib, Erlotinib, Afatinib
—> need to check subsequently to see whether tumour cells develop acquired resistance
Resistant T790M mutation in Exon 20
- resistant to 1st gen TKI
—> ***Osimertinib (3rd gen TKI)
ALK-positive NSCLC
ALK (Anaplastic Lymphoma Kinase) chromosomal translocation in NSCLC —> Oncogenic activation
- **Adenocarcinoma
- **Never / Light smokers
- ***Younger patients (median 50 yo)
- No sex differences
Investigations:
- ALK IHC (simpler)
- ALK FISH
ALK re-arranged / IHC +ve:
- ***Crizotinib (1st line)
- Ceritinib / Alectinib / Brigatinib / Lorlatinib / Systemic Chemo / Immuno (2nd line)
Immunotherapy: Immune-checkpoint inhibitor
Aimed at PDL1/PD1 axis
Monoclonal Ab targeting:
1. PDL1 (Programmed death-ligand 1) expression on **tumour cells
Or
2. PD1 expression on **cytotoxic T cells
—> block interaction between PDL1 and PD1
—> preserve cytotoxic action of T cells to tumour cells
Investigations / Monitoring:
- PDL1 IHC staining intensity
—> **Tumour proportional score (TPS): **>50% indicate better response to Anti-PDL1 therapy
Indications:
- Anti-PDL1 + Chemo in tumours with ***PDL1 expression (1st line)
- Anti-PDL1 alone (2nd line, no need for PDL1 test)
Drugs:
- ***Pembrolizumab, Nivolumab, Atezolizumab
Treatment flowchart for Advanced NSCLC (Asians)
EGFR mutant
1. Sensitising mutations (Del 19, L858R)
—> ***EGFR-TKI
—> Re-biopsy on progression
—> No new mutation
—> EGFR-TKI / Platinum-based chemotherapy +/- Bevacizumab (Anti-EGFR inhibitor)
—> New mutation (T790M mutant)
—> ***3rd gen EGFR-TKI
- Non-sensitising mutation (Exon 18, 20)
—> Platinum-based chemotherapy +/- Bevacizumab
EGFR wildtype
1. ALK rearrangement
—> ***Crizotinib
—> Disease progression
—> 2nd / 3rd gen ALK inhibitor
- No ALK rearrangement
—> Platinum-based chemotherapy +/- Bevacizumab
Alternative to Platinum-based chemotherapy +/- Bevacizumab:
- ***Immune-checkpoint inhibitor (1st line +/- Chemo / 2nd line setting esp. after Chemo)
Others gene mutations:
- ROS1 gene rearrangement
Supportive care
- Hospice care
- Analgesics
- Other symptomatic care e.g. Cough suppression, **Thoracentesis + **Pleurodesis
- Psychosocial support
