Pericardial Mesothelioma

Pericardial mesothelioma is a rare malignant tumour of the pericardial mesothelium. It usually presents with pericardial effusion, tamponade or constriction, is often diagnosed late or at autopsy, and has a median survival of about 6 months.

It forms under 1% of mesotheliomas and about half of primary cardiac malignant tumours. It is commoner in men (about 2 to 1), with a peak age in the 50s to 60s, and it occurs rarely in children.

Asbestos exposure is a weaker association than for pleural disease and is found in only a minority. Prior chest radiotherapy is reported. Many patients have no identified exposure.

Pathophysiology. Tumour cells arise from the mesothelium lining the pericardium, spread over the visceral and parietal surfaces, and encase the heart (constriction) or produce effusion. BAP1 and CDKN2A alterations are described.

Histological subtypes. Epithelioid, biphasic and sarcomatoid forms occur, like pleural mesothelioma. Epithelioid histology has the longer survival.

Behaviour. Local invasion of the myocardium and great vessels is frequent. Distant metastases (lung, lymph nodes, liver, kidney, brain) are found in about 30% to 40% at presentation or autopsy.

• Dyspnoea, chest pain, cough, fatigue, orthopnoea and palpitations.
• Signs of tamponade (raised jugular venous pressure, pulsus paradoxus, hypotension) or constriction (Kussmaul sign, ascites, oedema).
• Atrial arrhythmias, heart failure and superior vena cava obstruction.
• Haemorrhagic effusion that recurs after drainage, and a pericardial friction rub.

Red flags.

• Hypotension with raised venous pressure and muffled heart sounds (tamponade).
• Syncope, new arrhythmia or low cardiac output.

• Echocardiography: effusion, thickened pericardium, nodular masses and constrictive physiology. CT and cardiac MRI define pericardial thickening and nodularity, myocardial invasion and extracardiac spread. FDG-PET-CT assists staging.
• ECG: low voltage, arrhythmia.
• Pericardial fluid cytology is often negative (sensitivity under 30%). Biopsy through subxiphoid pericardial window, pericardioscopy or thoracoscopy gives tissue.
• Immunohistochemistry: calretinin, WT1, cytokeratin 5/6 and D2-40 positive, with BAP1 or MTAP loss.
• Pericardial fluid testing for infection (including tuberculosis), and blood tests including troponin, natriuretic peptide, creatinine and thyroid function.
• CT of the chest, abdomen and pelvis for staging.

Differential diagnosis.

• Metastatic pericardial disease from lung, breast or lymphoma
• Pericardial angiosarcoma, synovial sarcoma and other primary cardiac sarcomas
• Tuberculous pericarditis
• Idiopathic and radiation induced constrictive pericarditis
• Uraemic, autoimmune and IgG4-related pericarditis
• Pericardial cyst and thymic or germ cell tumour invading the pericardium

Management is individualised in a multidisciplinary team, with the aim of relieving haemodynamic compromise and prolonging life.

Drainage. Urgent pericardiocentesis for tamponade, with a drain left in place until output is under 50 mL in 24 hours. Recurrent effusion needs a subxiphoid pericardial window or percutaneous balloon pericardiotomy.

Surgery. Pericardiectomy with removal of tumour for constriction in fit patients with limited disease, in a specialised centre. Complete resection is rarely possible.

Systemic therapy.

• Cisplatin with pemetrexed: cisplatin 75 mg/m2 IV over 1 to 2 hours with pre-hydration and post-hydration, and pemetrexed 500 mg/m2 IV over 10 minutes, both on day 1 of a 21-day cycle for up to 6 cycles; supplementation: folic acid 400 micrograms orally once daily starting 7 days before the first dose and continuing until 21 days after the last, vitamin B12 1000 micrograms IM starting 1 week before the first dose and repeated every 9 weeks, dexamethasone 4 mg orally twice daily on the day before, the day of and the day after each pemetrexed dose; maximum cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 each cycle; monitoring: FBC, creatinine and electrolytes before each cycle, audiometry, neuropathy symptoms; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (substitute carboplatin AUC 5 IV on day 1 when it is lower), give pemetrexed only when clearance is 45 mL/min or more, stop NSAIDs from 2 days before to 2 days after each pemetrexed dose, hold for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L and resume at 75% of the dose In heart failure, hydration volume is reduced and carboplatin is preferred.
• Nivolumab with ipilimumab (preferred for non-epithelioid disease): nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks, for up to 24 months or until progression or unacceptable toxicity; maximum nivolumab 360 mg each 3-week dose and ipilimumab 1 mg/kg each 6-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis; adjustment: no renal or mild hepatic dose adjustment, withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily, stop permanently for grade 3 to 4 toxicity and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks

Radiotherapy. Palliative radiotherapy to the pericardium can control pain or bleeding but carries cardiac toxicity, so doses are limited.

Supportive care. Heart failure and arrhythmia management by a cardiologist, anticoagulation when thrombus or atrial fibrillation is present, and early palliative care.

Monitoring. Echocardiography every 2 to 4 weeks at first, CT every 8 to 12 weeks during treatment, and ejection fraction when using anthracycline containing or cardiotoxic regimens.

Referral and escalation.

• Referral to a cardio oncology and mesothelioma team after the first drainage.
• Emergency pericardiocentesis for tamponade.
• Urgent cardiology review for arrhythmia or heart failure.

Special groups.

• Renal impairment: carboplatin replaces cisplatin, and pemetrexed is avoided under 45 mL/min.
• Heart failure: avoid high volume hydration, and monitor fluid status daily.
• Pregnancy: rare, and managed by a multidisciplinary team.