Key Facts

Malignant pleural mesothelioma is an aggressive tumour arising from the mesothelial cells lining the pleural cavity. It is almost exclusively caused by asbestos exposure and is the most common primary malignancy of the pleura.

Epidemiology

• ~2,700 new cases per year in the UK (highest per capita worldwide)
• UK incidence peaked around 2018-2020; expected to decline slowly
• Male predominance (~4:1) reflecting occupational exposure patterns
• Median age at diagnosis: 70-75 years
• Latency period: 20-40 years from first asbestos exposure

Aetiology

• Asbestos exposure (>80%): occupational (construction, shipbuilding, insulation, plumbing); environmental; para-occupational (household contacts)
• Crocidolite (blue asbestos) > amosite (brown) > chrysotile (white) in carcinogenicity
• Non-asbestos causes: erionite (volcanic mineral), radiation, SV40 virus (debated)
• No dose threshold — even brief exposure can cause disease

Pathophysiology

• Asbestos fibres penetrate to pleural surface and cause chronic inflammation
• DNA damage from reactive oxygen species and frustrated phagocytosis
• Activation of oncogenic pathways (BAP1, NF2, CDKN2A loss)
• Tumour encases the lung (pleural rind), invading chest wall, diaphragm, and mediastinum
• Histological subtypes: epithelioid (60%, best prognosis), sarcomatoid (20%, worst prognosis), biphasic (20%)

Typical Presentation

• Progressive breathlessness (pleural effusion — 90% at presentation)
• Non-pleuritic chest wall pain (dull, persistent)
• Weight loss, fatigue, sweats
• Occupational asbestos exposure history (may be remote)

Clinical Signs

• Signs of pleural effusion: reduced expansion, stony dull percussion, reduced breath sounds
• Finger clubbing (~30%)
• Chest wall mass (advanced disease)
• Contralateral mediastinal shift (large effusion) or ipsilateral shift (trapped lung)

Advanced Disease

• Chest wall invasion: localised pain, palpable mass
• SVC obstruction
• Dysphagia (oesophageal compression)
• Pericardial involvement: effusion, tamponade
• Contralateral spread, peritoneal involvement

Red Flags

• Unilateral pleural effusion in patient with asbestos exposure history
• Non-resolving unilateral effusion
• Chest wall pain with effusion
• Pleural thickening >1cm on imaging

Bedside

• Pulse oximetry: baseline
• Occupational history: detailed asbestos exposure assessment

Bloods

• FBC, U&Es, LFTs: baseline
• CRP: elevated in some cases
• Mesothelin/fibulin-3: potential biomarkers (not yet routine)

Imaging

• CXR: unilateral pleural effusion ± pleural thickening; pleural plaques may be present
• CT chest (contrast-enhanced): nodular or circumferential pleural thickening, pleural effusion, mediastinal lymphadenopathy
• PET-CT: staging, assess metabolic activity, guide biopsy
• MRI chest: assess chest wall and diaphragmatic invasion (surgical planning)

Special Tests

• Pleural aspiration: exudative, often bloodstained; cytology sensitivity only ~30% (low sensitivity for mesothelioma)
• Thoracoscopic (VATS) pleural biopsy: gold standard for diagnosis — sensitivity >90%
• CT-guided percutaneous biopsy: alternative if VATS not possible
• Immunohistochemistry: calretinin+, WT1+, CK5/6+ (mesothelioma markers); CEA−, TTF-1− (excludes adenocarcinoma)
• BAP1 loss: supports mesothelioma diagnosis
• Pulmonary function tests: restrictive pattern if large effusion or trapped lung

Non-pharmacological

• MDT discussion: all cases at specialist mesothelioma MDT
• Compensation advice: refer for Industrial Injuries Disablement Benefit, civil litigation, and Diffuse Mesothelioma Payment Scheme
• Psychological support and palliative care early referral
• Smoking cessation (not causative but worsens lung function)

Pharmacological

First-line palliative chemotherapy:

• Pemetrexed 500mg/m² + cisplatin 75mg/m² every 21 days for up to 6 cycles (Vogelzang trial: improved median survival from 9 to 12 months)
• Pre-medicate with folic acid 400mcg daily and vitamin B12 1mg IM every 9 weeks to reduce pemetrexed toxicity
• Carboplatin substituted if cisplatin contraindicated

Immunotherapy:

• Nivolumab 360mg + ipilimumab 1mg/kg every 3 weeks for 4 cycles, then nivolumab 480mg every 4 weeks — first-line for non-epithelioid or PD-L1 ≥1% (CheckMate 743 trial; NICE TA781)

Symptom management:

• Pleural effusion: indwelling pleural catheter (IPC) or talc pleurodesis
• Pain: WHO analgesic ladder ± neuropathic agents (pregabalin, gabapentin)
• Palliative radiotherapy: prophylactic to biopsy/drain tract sites (debated)

Surgical/Interventional

• Pleurodesis (talc slurry via chest drain or thoracoscopic talc poudrage): for recurrent symptomatic effusion
• Indwelling pleural catheter (IPC): for trapped lung or recurrent effusion post-pleurodesis
• Extended pleurectomy/decortication (EPD): in highly selected patients; multimodal approach (MARS 2 trial ongoing)
• Extrapleural pneumonectomy: largely abandoned due to high morbidity/mortality (MARS trial)

Referral Criteria

• All suspected mesothelioma to specialist centre
• Early palliative care involvement
• Compensation/legal advice referral
• Specialist thoracic surgery opinion in selected early-stage disease

• Median overall survival: ~12 months from diagnosis
• Epithelioid: median ~18 months
• Sarcomatoid: median ~6-8 months
• Biphasic: median ~12 months
• Poor prognostic factors: sarcomatoid histology, advanced stage, poor performance status, raised WCC/platelet count, low Hb
• With pemetrexed/cisplatin: median survival ~12-14 months
• With nivolumab/ipilimumab (non-epithelioid): median survival ~18 months
• 5-year survival: <5% overall
• UK mesothelioma deaths expected to peak and then decline over coming decades as asbestos exposure diminishes

Asbestos-Related Conditions Spectrum

Mesothelioma Subtypes