Cancer - mesothelioma
Description
- Malignancy of mesothelial cells; pleura ~80-90%, peritoneum ~10%, rarely pericardium or tunica vaginalis
- Almost always asbestos-related - and therefore a medico-legal as well as a medical diagnosis
Histological subtypes - prognostically dominant
| Subtype | % | Median survival |
|---|---|---|
| Epithelioid | ~60% | ~18-24 mo (best; the only one considered for surgery) |
| Biphasic (mixed) | ~25% | ~12 mo |
| Sarcomatoid | ~15% | ~6-8 mo (worst; desmoplastic variant hardest to distinguish from fibrous pleuritis) |
- IHC: calretinin, WT-1, CK5/6, D2-40, mesothelin positive; TTF-1, CEA, claudin-4, Ber-EP4 negative (excludes adenocarcinoma)
- BAP1 loss and CDKN2A/p16 homozygous deletion distinguish malignant mesothelioma from reactive mesothelial hyperplasia
Epidemiology
- Australia has among the highest incidence in the world - ~700-800 cases/yr
- Legacy of Wittenoom crocidolite mining and heavy asbestos use in construction until 1980s; total ban since 2003
- M>F ~4:1; median age ~75
- Latency 20-50 years from exposure (mean ~40) - incidence has peaked but a long tail continues
- Third wave: home renovators and DIY exposure, not occupational
- No safe exposure threshold; risk is dose-related but not dose-dependent for causation
Aetiopathogenesis
Asbestos
- >80% have identifiable exposure - and a careful occupational, domestic and renovation history is mandatory
- Amphiboles (crocidolite "blue", amosite "brown") far more carcinogenic than chrysotile ("white") - long, thin, biopersistent fibres
- Mechanism: fibres reach the pleura -> chronic frustrated phagocytosis -> reactive oxygen species, chromosomal damage, HMGB1-driven chronic inflammation and IL-1beta
- Smoking does NOT increase mesothelioma risk (unlike asbestos-related lung cancer, where the interaction is multiplicative) - a common exam discriminator
Other causes
- Erionite (Cappadocia), therapeutic radiation, SV40 (disputed)
- Germline BAP1 mutation - mesothelioma, uveal melanoma, RCC, cutaneous melanocytic tumours
Somatic genetics
- BAP1, NF2, CDKN2A, TP53 loss; characterised by tumour suppressor loss, not activating oncogenes - hence no targetable driver
Diagnosis
Presentation
- *Unilateral pleural effusion + persistent chest wall pain (a dull ache that wakes the patient at night) = mesothelioma until proven otherwise*
- Progressive dyspnoea, weight loss, sweats
- Later: chest wall mass, rib invasion, encasement -> "frozen hemithorax" with volume loss and ipsilateral mediastinal shift towards the effusion
- Peritoneal: ascites, abdominal distension, obstruction
Imaging
- CXR - unilateral effusion, pleural thickening, pleural plaques (plaques mark exposure, not malignancy)
- CT chest with contrast - nodular pleural thickening, mediastinal pleural involvement, thickening >1 cm, circumferential rind, interlobar fissure involvement
- PET-CT for staging and biopsy targeting; MRI for chest wall/diaphragm invasion
Tissue is mandatory
- *Pleural fluid cytology alone is not sufficient* - sensitivity ~30-60% and cannot assess invasion
- Thoracoscopic (VATS/medical pleuroscopy) pleural biopsy is the gold standard - large samples, direct visualisation, allows talc pleurodesis at the same sitting
- CT-guided core biopsy if pleuroscopy not feasible
- Biopsy tracts seed - mark them; prophylactic radiotherapy no longer routine (SMART/PIT trials negative)
- Mesothelin is not sensitive or specific enough to diagnose
Staging
- TNM (IMIG); staging is poorly reproducible and rarely changes management outside a surgical program
Management
Palliative intent in nearly all patients. Multidisciplinary from the outset.
A. Systemic therapy
- First line: nivolumab + ipilimumab (CheckMate 743) - OS benefit over chemotherapy, and the effect is largest in non-epithelioid disease
- Or platinum + pemetrexed (cisplatin/carboplatin + pemetrexed, +/- bevacizumab)
- Still preferred by some in epithelioid disease
- Pemetrexed requires folic acid + B12 supplementation to reduce myelosuppression and mucositis
- Second line: whichever modality was not used first; then vinorelbine, gemcitabine
- Enrol in a clinical trial wherever possible
B. Local control of the effusion - the main symptomatic problem
- Talc pleurodesis at thoracoscopy if the lung re-expands
- Indwelling pleural catheter if trapped lung or repeated reaccumulation - can be managed at home
- Repeated therapeutic aspiration only for the very frail
C. Surgery
- No survival benefit demonstrated
- Extrapleural pneumonectomy is essentially abandoned (MARS - high morbidity, possible harm)
- Pleurectomy/decortication in highly selected epithelioid, early-stage, fit patients within a trial or expert centre (MARS-2 did not show benefit)
D. Radiotherapy
- Palliative for chest wall pain and symptomatic sites
- Not curative; no role for routine prophylactic tract irradiation
E. Symptom control - the core of management
- Pain is neuropathic and somatic - opioid + adjuvant (gabapentinoid, TCA); consider intercostal nerve block, cordotomy for refractory pain
- Breathlessness - drain, opioids, fan, pulmonary rehabilitation
- Early palliative care referral
F. Medico-legal and compensation - part of the treating team's job
- Notify and refer for compensation early - it materially affects the family
- Dust diseases / workers compensation schemes (state-based)
- Asbestos-related disease boards and registers
- Notifiable to the Australian Mesothelioma Registry
- Document exposure history in detail while the patient is well enough to give it
Associations
- Asbestos exposure - occupational (mining, shipbuilding, construction, boilermaking, plumbing, electrical, brake linings), domestic (washing work clothes), and renovation
- Other asbestos-related disease: pleural plaques (marker of exposure only), diffuse pleural thickening, benign asbestos pleural effusion, rounded atelectasis, asbestosis, and asbestos-related lung cancer (multiplicative interaction with smoking)
- Germline BAP1 tumour predisposition - uveal melanoma, RCC, cutaneous melanocytic tumours
- Erionite exposure, prior thoracic radiotherapy
- Not associated with smoking
Natural history & complications
- Median survival ~12 months from diagnosis overall
- Epithelioid ~18-24 mo; sarcomatoid ~6 mo
- Improved to ~18 mo with immunotherapy in non-epithelioid disease
- Poor prognostic factors: sarcomatoid histology, poor performance status, weight loss, chest pain, high WCC/platelets, low haemoglobin, male sex, age
Progression
- Local, relentless: circumferential pleural encasement -> trapped lung, chest wall invasion, rib destruction
- Transdiaphragmatic and mediastinal spread; contralateral pleura late
- Distant metastasis uncommon and usually late
- Death is usually from progressive respiratory failure or refractory chest wall pain, not metastatic disease
Complications
- Recurrent effusion, trapped lung, pneumothorax
- Intractable neuropathic chest wall pain
- SVC obstruction, pericardial involvement, dysphagia
- Small bowel obstruction (peritoneal disease)
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