Respiratory JC018: Pleural Effusion In A Chronic Smoker: Pleural Effusion, Lung Cancer Flashcards

1
Q

Case: 64 yo male, chronic smoker, retired restaurant worker

A
  • 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

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2
Q

Pathophysiology of pleural effusion

A

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)

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3
Q

Hydrostatic pressure

A

↑ due to abnormal fluid retention:
1. **Congestive HF
2. **
Renal failure
3. Other forms of volume overload

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4
Q

Oncotic pressure

A

↓ mainly due to ↓ plasma protein (esp. Albumin):
1. **Cirrhosis
2. **
Nephrotic syndrome
3. Severe malnutrition
4. ***Other forms of hypoalbuminemia

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5
Q

Capillary permeability

A

↑ 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)

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6
Q

Lymphatic drainage

A

↓ due to:
1. ***Malignant infiltration of mediastinal, pulmonary, pleural lymphatics
—> ↑ pressure in downstream lymphatics

  1. Necrotising / ***Granulomatous infections
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7
Q

***Transudative vs Exudative fluid

A

Transudative:
1. ↑ Hydrostatic pressure
2. ↓ Oncotic pressure
—> ***Pure water movement

Exudative:
1. ↑ Capillary permeability
2. ↓ Lymphatic drainage
—> Direct leakage
—> ***Protein movement also

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8
Q

***Investigations of Transudative vs Exudative fluid

A

Diagnostic thoracentesis (aka pleural tapping) + ***Pleural fluid analysis

記: ABCCM

  1. ***Appearance
    - turbid
    - blood stained
    - clear / straw colour
  2. Biochemistry
    - ***Protein + LDH (Light’s criteria)
    - Glucose, pH
  3. ***Cell count + differential
    - Empyema: Neutrophil predominant
    - Tuberculous pleurisy: Lymphocyte predominant
  4. ***Cytology
    - malignancy / atypical cells
    (- 70% yield (CL Lai))
  5. ***Microbiology
    - smear for AFB / other bacteria
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9
Q

***Light’s criteria

A

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

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10
Q

Other investigations

A
  1. Percutaneous pleural biopsy
    - ***exudative effusion
    - esp. to confirm TB / cancer
  2. Thoracoscopy / ***Pleuroscopy

Aim: Identification of primary cause of pleural fluid formation

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11
Q

Lung cancer epidemiology

A

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

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12
Q

Pathogenesis of Adenocarcinoma and SCC

A

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

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13
Q

***WHO classification of lung tumour histology

A

Epithelial tumours:
1. Non-small cell lung cancer (85%)
- Adenocarcinoma (45-55%)
- SCC (20-30%)
- Large cell carcinoma (5-10%)

  1. Small cell lung cancer (5-10%)
  2. Mixed

Mesothelial tumours:
1. Malignant mesothelioma

Miscellaneous malignant tumours

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14
Q

***Clinical presentation of lung cancer

A

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

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15
Q

***S/S of lung cancer

A
  1. Radiological abnormality only
  2. ***Constitutional symptoms
    - malaise
    - ↓ appetite
    - ↓ body weight
  3. Primary lesion
    - Bronchial mucosa ulceration
    —> cough, sputum, ***haemoptysis
  • **Obstructive
    —> partial: **
    wheeze, unresolved pneumonia, dyspnea
    —> complete: ***lung collapse
  1. 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
  2. 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
  3. 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)
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16
Q

***Investigations of lung cancer

A

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

  1. Cytology
    - **sputum
    - **
    bronchial washing + brushing
    - pleural fluid
    - fine needle aspiration
  2. Histology (better classify subtype + molecular genetic testing)
    - **bronchoscopic biopsy: bronchial / transbronchial
    - pleura
    - LN
    - metastatic sites
    - **
    exploratory thoracotomy
  3. 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
17
Q

PET-CT

A
  • 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)
18
Q

***Other Pulmonary interventions (besides bronchoscopy)

A

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

19
Q

Endobronchial ultrasound (EBUS)

A
  • 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)

  1. Alternative diagnosis for ***mediastinal lymphadenopathy
    —> TB, sarcoidosis, lymphoma
  2. ***Tumour mass immediately adjacent to accessible part of airway through EBUS bronchoscope
20
Q

Staging for Non-small cell lung cancer

A

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)

21
Q

***Treatment for lung cancer

A

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

22
Q

***Chemotherapy

A

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

23
Q

Differentiate histology type: Adenocarcinoma

A

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)

24
Q

Mutations of Adenocarcinoma

A

Asians:
- ***EGFR (55%)
- KRAS (5-10%)

Caucasians:
- KRAS (30%)
- EGFR (10-15%)

25
Q

***Molecular targeted therapy

A

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

  1. Resistant EGFR T790M mutation
    - ***Osimertinib
  2. EML4-ALK gene rearrangement
    - ***Crizotinib
    - Ceritinib
    - Alectinib
  3. ROS1 gene rearrangement
    - Crizotinib
26
Q

***EGFR Tyrosine Kinase Inhibitors (TKI)

A

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)

27
Q

ALK-positive NSCLC

A

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)

28
Q

Immunotherapy: Immune-checkpoint inhibitor

A

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

29
Q

Treatment flowchart for Advanced NSCLC (Asians)

A

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

  1. Non-sensitising mutation (Exon 18, 20)
    —> Platinum-based chemotherapy +/- Bevacizumab

EGFR wildtype
1. ALK rearrangement
—> ***Crizotinib
—> Disease progression
—> 2nd / 3rd gen ALK inhibitor

  1. 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

30
Q

Supportive care

A
  • Hospice care
  • Analgesics
  • Other symptomatic care e.g. Cough suppression, **Thoracentesis + **Pleurodesis
  • Psychosocial support