Primary malignancies of the lung and pleura
Description
Histology - the first branch point
| Share | Key features | |
|---|---|---|
| Adenocarcinoma | ~40% | Peripheral, spiculated margins; commonest in never-smokers and in women; metastasises early; may cavitate. Driver mutations concentrate here |
| Squamous cell | ~25-30% | Central, endobronchial; strongly smoking-related; cavitates; PTHrP -> hypercalcaemia |
| Small cell (SCLC) | ~15% | Central, bulky mediastinal nodes; neuroendocrine; almost exclusively smokers; SIADH, ectopic ACTH, LEMS |
| Large cell | ~5-10% | Poorly differentiated, peripheral, aggressive |
| Carcinoid | ~2% | Central, well-vascularised endobronchial; bleeds at bronchoscopy; indolent (typical) |
- NSCLC = adeno + squamous + large cell. Treated by stage and molecular profile
- SCLC = a systemic disease at presentation. Treated by limited vs extensive stage
- Spiculated peripheral margins favour a primary; smooth round lesions favour a metastasis**
Pleural malignancy
- Malignant pleural mesothelioma - the primary pleural cancer; asbestos
- Epithelioid (~60%, best prognosis) / sarcomatoid (worst) / biphasic
- Metastatic pleural disease is far commoner than mesothelioma - lung, breast, lymphoma, ovary
- Rare: solitary fibrous tumour of pleura (may cause hypoglycaemia via IGF-2), pleural lymphoma
Epidemiology
- Lung cancer: the leading cause of cancer death in Australia (~8,700 deaths/yr) despite being the 5th commonest cancer
- Smoking causes ~80-90%; risk falls after cessation but never to baseline
- Never-smoker lung cancer is rising - adenocarcinoma, more often women and people of East Asian ancestry, enriched for EGFR and ALK alterations
- 5-year survival all stages ~20-25% in Australia; stage I ~70-90%, stage IV <5%
- Mesothelioma: ~700-800 Australian cases/yr - among the highest rates in the world
- M>F (~4:1), median age ~75, latency 20-50 years from exposure
- Third wave of exposure now from home renovation, not occupational mining/manufacture
Aetiopathogenesis
Lung cancer risk factors
- Tobacco smoking - dose and duration dependent; pack-years the working measure
- Asbestos (multiplicative with smoking - ~50x risk combined), radon, silica, arsenic, chromium, nickel, diesel exhaust, polycyclic aromatic hydrocarbons
- COPD and pulmonary fibrosis - independent of smoking
- Prior chest radiotherapy, previous aerodigestive malignancy
- Family history, HIV, indoor biomass fuel smoke, air pollution
Molecular drivers - test every non-squamous NSCLC
| Alteration | Frequency | Targeted agent |
|---|---|---|
| EGFR (exon 19 del, L858R) | 10-15% (up to 50% East Asian, never-smokers) | Osimertinib |
| ALK rearrangement | ~5% | Alectinib, lorlatinib, brigatinib |
| KRAS G12C | ~13% | Sotorasib, adagrasib |
| ROS1 | 1-2% | Crizotinib, entrectinib |
| BRAF V600E | 2% | Dabrafenib + trametinib |
| MET exon 14 skipping, RET, NTRK, HER2 | 1-3% each | Capmatinib/tepotinib, selpercatinib, larotrectinib, trastuzumab deruxtecan |
| PD-L1 expression | - | Determines immunotherapy strategy |
- Driver mutations and PD-L1 are largely mutually informative: do not start immunotherapy before molecular results in a never-smoker with adenocarcinoma - EGFR/ALK-positive disease responds poorly to checkpoint inhibitors and has increased toxicity with sequential use
Mesothelioma
- Asbestos fibres (amphiboles - crocidolite, amosite - more carcinogenic than chrysotile) reach the pleura -> chronic inflammation, ROS, frustrated phagocytosis
- BAP1, NF2, CDKN2A loss are the characteristic somatic events
- Germline BAP1 tumour predisposition syndrome - mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma
- No dose threshold; even brief exposure can suffice. Not related to smoking (unlike lung cancer)
Diagnosis
Presentation
- Local: cough, haemoptysis, dyspnoea, chest pain, recurrent or non-resolving pneumonia, stridor/wheeze
- Regional: hoarseness (left recurrent laryngeal), SVC obstruction, dysphagia, Horner syndrome + T1 wasting/pain = Pancoast tumour, phrenic palsy, pericardial or pleural effusion
- Metastatic: bone pain, headache/seizure/focal deficit, hepatomegaly, adrenal (usually silent)
- Constitutional: weight loss, anorexia, fatigue
- Mesothelioma: insidious, unilateral non-pleuritic chest wall pain plus breathlessness from effusion, with weight loss and sweats. Pain out of proportion to the effusion is the clue
Paraneoplastic syndromes
| Syndrome | Histology |
|---|---|
| SIADH | SCLC |
| Ectopic ACTH (hypokalaemic alkalosis, rapid onset, no classic Cushingoid habitus) | SCLC |
| Lambert-Eaton myasthenic syndrome (VGCC antibodies, power improves with use) | SCLC |
| Paraneoplastic cerebellar degeneration, encephalomyelitis (anti-Hu) | SCLC |
| Hypercalcaemia (PTHrP) | Squamous |
| Hypertrophic pulmonary osteoarthropathy - clubbing + painful periostitis of long bones | Adenocarcinoma / NSCLC |
| Dermatomyositis, migratory thrombophlebitis (Trousseau), acanthosis nigricans | Any |
Investigation sequence
1. CXR then CT chest/upper abdomen with contrast (adrenals, liver)
2. PET-CT for staging in potentially curable disease
3. MRI brain - all SCLC, and stage II+ NSCLC (or any neurological symptom)
4. Tissue - the modality that gives both diagnosis and the highest stage:
- EBUS-TBNA for mediastinal nodes (stages and diagnoses in one procedure)
- Bronchoscopy for central lesions; CT-guided biopsy for peripheral
- Pleural fluid cytology, thoracoscopy (pleuroscopy) for pleural disease
5. Molecular and PD-L1 testing on all non-squamous NSCLC (and squamous in never-smokers)
6. Fitness: spirometry + DLCO; if ppoFEV1 or ppoDLCO <60% -> CPET
Mesothelioma - diagnostic specifics
- Pleural fluid cytology alone is often insufficient (sensitivity ~30-50%) -> thoracoscopic pleural biopsy is the diagnostic standard
- CT: circumferential nodular pleural thickening, mediastinal pleural involvement, thickening >1 cm, volume loss of the hemithorax
- Immunohistochemistry: calretinin, WT-1, CK5/6, D2-40 positive; TTF-1, CEA, claudin-4 negative (separates from adenocarcinoma)
- Loss of BAP1 nuclear staining and CDKN2A deletion by FISH distinguish malignant from reactive mesothelial proliferation
- Avoid repeated blind pleural procedures - tract seeding
Staging
- NSCLC: TNM 9th edition - note the N2 category is now subdivided (N2a single-station, N2b multi-station) and M1c split by organ involvement
- SCLC: limited (confined to one hemithorax within a tolerable radiation field) vs extensive; TNM also applied
- Mesothelioma: TNM; T stage driven by depth of invasion, and staging is poorly reproducible
Management
A. Screening - National Lung Cancer Screening Program, live since July 2025
- Eligibility: age 50-70, >=30 pack-year history, currently smoking or quit within the past 10 years, and no signs or symptoms of lung cancer
- Free biennial low-dose CT, with a defined nodule management pathway
- Underpinned by NLST and NELSON (~20% dec lung cancer mortality)
- Screening must be coupled with smoking cessation support - the two effects are additive
B. NSCLC - by stage
- Stage I-II (localised): surgical resection (lobectomy + systematic nodal dissection); SABR/stereotactic radiotherapy if medically inoperable
- Adjuvant chemotherapy for stage IB (high risk) to III; adjuvant osimertinib if EGFR-mutant (ADAURA); adjuvant/perioperative immunotherapy in PD-L1-positive resected disease
- Neoadjuvant chemo-immunotherapy (CheckMate 816 and successors) is now standard in resectable stage II-IIIA
- Stage III (locally advanced): concurrent chemoradiotherapy followed by consolidation durvalumab (PACIFIC); selected patients go to surgery after induction therapy
- Stage IV (metastatic):
- Driver mutation present -> targeted therapy first (osimertinib, alectinib, etc.)
- No driver -> PD-L1-guided: high PD-L1 -> pembrolizumab monotherapy; otherwise chemo-immunotherapy
- Local therapy for oligometastatic disease; bone-modifying agents for bone metastases
- Palliative radiotherapy for haemoptysis, pain, SVC obstruction, brain metastases
C. SCLC
- Limited stage: concurrent chemoradiotherapy (platinum-etoposide), then consider prophylactic cranial irradiation (PCI)
- Extensive stage: platinum-etoposide + a PD-L1 inhibitor (atezolizumab or durvalumab); thoracic consolidation RT and PCI in selected
- Exquisitely chemosensitive and equally quick to relapse - response rates are high, durability is not
D. Mesothelioma
- Unresectable / most patients: first-line nivolumab + ipilimumab - superior overall survival vs chemotherapy (CheckMate 743: median OS 18.1 vs 14.1 months; 2-yr 41% vs 27%), benefit across histologies and greatest in non-epithelioid
- Alternative/second-line: platinum + pemetrexed (+/- bevacizumab)
- Surgery (pleurectomy-decortication, EPP) - MARS-2 showed no survival benefit from extended pleurectomy-decortication added to chemotherapy; surgery is now largely confined to trials and to symptom control
- Pleural effusion control - talc pleurodesis or indwelling pleural catheter (IPC preferred with trapped lung)
- Prophylactic radiotherapy to procedure tracts is NOT routinely recommended (SMART/PIT trials)
- Analgesia is central - neuropathic agents, intercostal/paravertebral blocks, early palliative care
- Compensation - occupational exposure history is medico-legally important; refer for dust disease compensation (state schemes, Comcare, ADDS)
E. Everyone
- Smoking cessation at every point - improves treatment tolerance and survival even after diagnosis
- Early specialist palliative care improves quality of life and survival in metastatic NSCLC (Temel)
- Lung cancer nurse coordinator, MDT discussion for every case
- Nutrition, VTE risk (high), management of malignant pleural effusion and airway obstruction (stenting, brachytherapy)
Associations
- Asbestos exposure - mesothelioma, lung cancer, asbestosis, benign pleural plaques, diffuse pleural thickening, benign asbestos pleural effusion, rounded atelectasis
- Pleural plaques are a marker of exposure, not a premalignant lesion
- COPD and pulmonary fibrosis - both independently increase lung cancer risk
- Germline BAP1 - mesothelioma, uveal melanoma, RCC
- Li-Fraumeni, retinoblastoma survivors - increased risk with prior radiotherapy
- Immunotherapy toxicity - pneumonitis, colitis, thyroiditis, hypophysitis, hepatitis, myocarditis
- TKI toxicity - EGFR (rash, diarrhoea, ILD, QT), ALK (hepatitis, ILD, lorlatinib CNS and lipid effects)
- VTE - lung adenocarcinoma is a high-risk malignancy
Natural history & complications
- NSCLC 5-year survival by stage: I ~70-90%, II ~50%, III ~15-35%, IV <5% (improving with targeted and immune therapy - some EGFR/ALK patients now live years)
- SCLC: limited stage median survival ~20-25 months; extensive stage ~12 months with chemo-immunotherapy
- Mesothelioma: median survival ~12 months untreated, ~18 months with nivolumab-ipilimumab; epithelioid better, sarcomatoid worst (~6 months)
- Two-thirds of Australian lung cancers are diagnosed at stage III or IV - the rationale for the screening program
Complications
- SVC obstruction, massive haemoptysis, central airway obstruction
- Malignant pleural effusion (recurrent, symptomatic) and trapped lung
- Brain metastases (especially SCLC and adenocarcinoma), spinal cord compression, pathological fracture
- Hypercalcaemia, SIADH, ectopic ACTH
- Cachexia, VTE, febrile neutropenia
- Immune-related adverse events and radiation pneumonitis/oesophagitis
- Post-thoracotomy pain syndrome
Follow-up
- Surveillance CT after curative-intent treatment (commonly 6-monthly for 2-3 years, then annually)
- Second primary lung cancer ~1-2%/yr after cure - continued surveillance and cessation support
- Screen for and treat depression - prevalence is high and under-recognised
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access