Primary Cardiac Angiosarcoma

Primary cardiac angiosarcoma is a malignant vascular tumour arising in the heart, usually the right atrium, that invades the myocardium and pericardium and metastasises early. It is the commonest primary malignant cardiac tumour, accounting for about one third of cardiac sarcomas.

Primary cardiac tumours are rare, found in under 0.1% of autopsies, and about 25% are malignant. Angiosarcoma presents mostly in men aged 30 to 50. The right atrium is the site in about 70 to 80%, often near the right coronary artery and the atrioventricular groove, with extension through the wall into the pericardium.

Metastases are present in about 40 to 70% at diagnosis, to the lungs, liver, bone, lymph nodes and brain. Median survival is about 6 to 12 months, and 5-year survival is under 10 to 15% even with resection.

No definite cause is known. Inherited and radiation associated forms are described, and radiation to the chest is a risk factor.

Pathophysiology.

The tumour arises from endothelial cells and forms irregular vascular channels that infiltrate the atrial wall. It produces a bulky, haemorrhagic, friable mass that obstructs the tricuspid valve and the venae cavae, and invades the pericardium causing bloody effusion and tamponade.

Tumour embolisation and haematogenous spread cause early metastases. Invasion of the conduction system causes arrhythmia, and invasion of coronary arteries causes ischaemia. Very rich vascularity makes biopsy and resection hazardous.

Molecular features include abnormalities in angiogenic signalling (VEGF signalling, KDR and PLCG1 alterations) in some tumours, which underlies the interest in anti-angiogenic drugs.

Right heart failure (dyspnoea, oedema, ascites, raised jugular venous pressure), bloody pericardial effusion with tamponade, chest pain, palpitations and atrial arrhythmia, superior vena cava syndrome, syncope, cyanosis (right-to-left shunt), pulmonary or systemic emboli, fever, weight loss and fatigue. Presentation is often rapid, over weeks. Some patients are found with metastatic symptoms (cough, haemoptysis, bone pain, headache).

• Echocardiography: a right atrial mass, often broad based and infiltrating the free wall or the atrioventricular groove, with pericardial effusion and tricuspid obstruction.
• Cardiac MRI: heterogeneous mass with early high signal on T1 (haemorrhage), a "cauliflower" or "sunray" pattern on enhancement (vascular channels), and invasion of the pericardium and adjacent structures. CT shows extent and metastases, and coronary involvement.
• PET-CT for staging and a biopsy target. CT of chest, abdomen and pelvis, and MRI of brain for staging.
• Tissue diagnosis is required: biopsy through the transvenous endomyocardial route, thoracoscopy or surgical approach, with high vascularity making bleeding and tamponade risks significant. Pericardial fluid cytology is often negative.
• Immunohistochemistry: positive CD31, CD34, ERG and FLI1 (and factor VIII), negative cytokeratin in most, and high Ki-67 proliferation. Molecular profiling when systemic therapy is planned.
• Blood tests: full blood count, LDH, creatinine, liver tests, coagulation screen, troponin and NT-proBNP.

Differential diagnosis.

• Atrial myxoma and thrombus.
• Other cardiac sarcomas (undifferentiated pleomorphic sarcoma, leiomyosarcoma, rhabdomyosarcoma) and primary cardiac lymphoma.
• Pericardial mesothelioma and metastatic tumour (lung, breast, melanoma).
• Haemangioma, lipoma and haemorrhagic pericardial effusion of other cause.

Plan in a multidisciplinary sarcoma and cardiac surgery team early. Treatment is palliative in most patients.

Emergencies.

• Tamponade: echocardiography directed pericardiocentesis with a pigtail catheter, or surgical drainage, with oxygen, crystalloid 250 to 500 mL over 10 to 15 minutes, and noradrenaline 0.05 to 0.5 microgram/kg/min if hypotensive. Avoid diuretics and positive pressure ventilation where possible. Fluid is often bloody and recurs.
• Tricuspid obstruction or superior vena cava obstruction: urgent surgical debulking or stenting by the heart team.
• Arrhythmia: treat by type; avoid class I drugs in structural disease; amiodarone 300 mg intravenously over 20 to 60 minutes then 900 mg over 24 hours through a central line.

Surgery.

• Complete resection with negative margins (R0) is the only potentially curative approach, and is possible in a minority with localised disease, usually after neoadjuvant chemotherapy to shrink the tumour. Reconstruction of the atrium and valves is complex, and may need cardiopulmonary bypass. Heart transplantation is not used because of early recurrence.
• Palliative debulking relieves obstruction and effusion in selected patients.

Systemic therapy (for metastatic or unresectable disease, and neoadjuvant or adjuvant use).

• Doxorubicin 60 to 75 mg/m2 intravenously on day 1 every 21 days, for up to 6 cycles, with a cumulative ceiling of 450 to 550 mg/m2 (lower with prior chest radiation or cardiac disease). Measure echocardiographic ejection fraction before each cycle and stop for a fall to under 50% or a drop of 10 percentage points or more. Dexrazoxane at 10 times the doxorubicin dose, given as a short infusion before each dose, can be added once the cumulative dose reaches about 300 mg/m2. Antiemetics (5-HT3 antagonist, NK1 antagonist and dexamethasone), and full blood count before each cycle.
• Doxorubicin with ifosfamide: doxorubicin 75 mg/m2 on day 1 plus ifosfamide 10 g/m2 in each cycle (2.5 g/m2 daily on days 1 to 4, with mesna at 100% of the ifosfamide dose) every 21 days, with G-CSF support. Monitor creatinine, urine for haematuria, neurological status and sodium. Avoid ifosfamide when creatinine clearance is under 30 mL/min.
• Paclitaxel 80 mg/m2 intravenously on days 1, 8 and 15 every 28 days, with premedication (dexamethasone, chlorphenamine and an H2 antagonist). Active in angiosarcoma and used first line or after anthracyclines. Monitor full blood count, liver tests and neuropathy; reduce in hepatic impairment.
• Gemcitabine 900 to 1000 mg/m2 on days 1 and 8 with docetaxel 75 to 100 mg/m2 on day 8, every 21 days, is an alternative after anthracycline failure.
• Pazopanib 800 mg orally once daily on an empty stomach (reduce to 200 mg daily in moderate hepatic impairment; avoid in severe), monitoring blood pressure, ALT and bilirubin every 2 weeks for 2 months, then monthly, and thyroid function and ECG for QTc. Used for progressive metastatic disease after chemotherapy. Interactions with strong CYP3A4 inhibitors and inducers.
• Immunotherapy and other targeted agents are investigational outside specialist programmes.

Radiotherapy. For palliation of symptomatic masses and bone or brain metastases, and in selected adjuvant settings, with limits on cardiac dose and attention to additive cardiotoxicity with anthracyclines.

Supportive care.

• Anticoagulation for thrombus or atrial fibrillation only when bleeding risk allows, given the vascular tumour and haemorrhagic effusion (apixaban 5 mg twice daily, 2.5 mg twice daily if two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over).
• Right heart failure: furosemide 20 to 80 mg orally daily, with spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30 mL/min/1.73 m2; check at 1 and 4 weeks); avoid over diuresis.
• Early palliative care input and goals-of-care discussion at diagnosis, because prognosis is short.

Monitoring. Imaging (CT chest, abdomen and pelvis, with echocardiography or MRI) every 2 to 3 cycles of treatment. Ejection fraction before each anthracycline cycle. Full blood count, creatinine and liver tests before each cycle. Symptoms and drain output after pericardiocentesis.

Referral and escalation. Refer every suspected case at once to a tertiary cardiac centre with sarcoma expertise. Emergency referral for tamponade, tricuspid or caval obstruction, arrhythmia or shock.

Special groups.

• Pregnancy: rare; avoid doxorubicin, ifosfamide and pazopanib where possible, and decide with oncology, obstetrics and the patient.
• Young adults: fertility preservation before chemotherapy.
• Kidney impairment: avoid ifosfamide at creatinine clearance under 30 mL/min and adjust gemcitabine and docetaxel by specialist advice.
• Older adults: lower intensity regimens such as weekly paclitaxel, and early goals-of-care discussion.