Malignant Mesothelioma
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Direct answer
A primary tumour of the pleural (or peritoneal) mesothelium, strongly linked to asbestos exposure with a latency of 20 to 40 years or more — amphibole fibres such as crocidolite carrying the highest risk — malignant mesothelioma presents with progressive breathlessness from effusion, chest wall pain and weight loss, and is confirmed by image-guided biopsy with immunohistochemistry. Epithelioid histology carries the best prognosis and sarcomatoid the worst; treatment combines chemotherapy, immunotherapy and pleurodesis.
What you must remember
- Exposure sources: shipbuilding and ship repairs, asbestos cement and insulation, textile and brake-lining manufacture, and domestic or neighbourhood exposure from workers' clothing; the mineral erionite and prior radiation are recognised secondary associations, and a familial (BAP1 germline) predisposition exists.
- Clinical picture: insidious dyspnoea and non-pleuritic chest pain with a blood-stained exudative effusion; later, a fixed contracted hemithorax, chest wall masses, weight loss and ascites in peritoneal disease.
- Imaging: computed tomography shows nodular and circumferential pleural thickening — a rind encasing the lung with fissure involvement, volume loss and mediastinal pleural disease; magnetic resonance imaging or positron-emission tomography assists staging of chest wall and nodal involvement.
- Diagnosis: pleural fluid cytology alone is often insufficient; image-guided cutting-needle core biopsy of parietal pleura is standard, with thoracoscopy when needed — tract seeding is recognised and prophylactic port-site radiotherapy is largely abandoned.
- Immunohistochemistry separates the mimics: mesothelioma expresses calretinin, WT1, cytokeratin 5/6 and D2-40, while lacking the carcinoma markers Ber-EP4 and claudin-4; loss of BAP1 by immunohistochemistry and homozygous deletion of CDKN2A (p16) by fluorescence in situ hybridisation distinguish malignant from benign mesothelial proliferation — invaluable when cytology is ambiguous.
- Histological subtypes drive prognosis: epithelioid (commonest, best survival), sarcomatoid (worst) and biphasic (intermediate, needing adequate sampling).
- Treatment: first-line platinum-pemetrexed chemotherapy with or without bevacizumab; nivolumab plus ipilimumab immunotherapy is an established first-line option from the CHECKMATE-743 trial; talc pleurodesis or an indwelling catheter controls effusion; surgery (pleurectomy-decortication in selected early epithelioid disease) remains debated, and extrapleural pneumonectomy has fallen from favour; the disease remains incurable in most, with median survival around a year in historical series.
From a dockyard history of decades ago to a diagnosis
A 67-year-old who worked in ship repairs forty years ago presents with breathlessness and chest wall pain; the CT shows nodular, circumferential pleural thickening — a rind encasing the lung, with fissure involvement, volume loss and mediastinal pleural disease — alongside a blood-stained exudative effusion. The exposure history is the foundation: shipbuilding and repairs, asbestos cement and insulation, textile and brake-lining manufacture, or domestic exposure from a worker's clothing. The first immunohistochemistry question is mesothelioma versus metastatic adenocarcinoma, which far outnumbers it: mesothelioma expresses calretinin, WT1, cytokeratin 5/6 and D2-40 while lacking Ber-EP4 and claudin-4. The second is malignant versus benign mesothelial proliferation — what BAP1 loss and homozygous CDKN2A (p16) deletion were developed to resolve. Histology then sets the prognosis: epithelioid commonest and best, sarcomatoid worst, biphasic intermediate. Treatment is palliative in intent — platinum-pemetrexed with or without bevacizumab, or nivolumab plus ipilimumab as an established first-line option — with talc pleurodesis or an indwelling catheter for the effusion; the disease remains incurable in most, with median survival around a year in historical series.
Where students slip
The chief confusion is metastatic adenocarcinoma involving the pleura, and the settled answer is the immunohistochemistry panel, not the radiograph — calretinin and WT1 positive, Ber-EP4 and claudin-4 negative. The second error is over-calling benign reactive mesothelial proliferation, which is precisely what BAP1-p16 testing exists to adjudicate. The asbestos relationship is the third: pleural plaques indicate exposure, but the tumour arises from retained fibres, not from the plaques, and asbestosis is not a prerequisite — a question implying "plaques become mesothelioma" is testing exactly that distinction. The tested one-liners: latency 20 to 40 years, the rind-like thickening, the histology-prognosis hierarchy, nivolumab-ipilimumab as current first-line systemic therapy, and peritoneal disease as the non-pleural presentation.
Frequently asked questions
What exposure causes malignant mesothelioma?
Asbestos, especially amphibole crocidolite fibres, with a latency of 20 to 40 or more years from first exposure.
How is the diagnosis established?
Image-guided cutting-needle core biopsy with immunohistochemistry, since pleural fluid cytology is often inconclusive.
Which markers favour mesothelioma over metastatic adenocarcinoma?
Positivity for calretinin, WT1, cytokeratin 5/6 and D2-40 with negativity for Ber-EP4 and claudin-4.
Which tests separate benign from malignant mesothelial proliferation?
Loss of BAP1 expression and homozygous CDKN2A (p16) deletion, which indicate malignancy.
Which histological subtype has the worst prognosis?
Sarcomatoid mesothelioma, with epithelioid the best and biphasic intermediate.
What systemic therapy is used first-line?
Platinum-pemetrexed chemotherapy or nivolumab-ipilimumab immunotherapy, alongside pleurodesis for effusion control.