Intimal Sarcoma

Intimal sarcoma is a rare, aggressive sarcoma that arises from the intimal layer of large arteries, most often the pulmonary artery trunk and its main branches, and less often the aorta, with occasional cardiac origin. It grows along the lumen and mimics thromboembolic disease.

Incidence is about 1 case in 1,000,000 people each year or fewer. Median age is in the 50s to 60s, with a slight female predominance. Diagnosis is typically delayed for months.

No predisposing condition is established.

Pathophysiology. MDM2 amplification (about 70% to 80%) with CDK4 co-amplification is the commonest alteration, with EGFR, PDGFRA and CDK4 amplification in subsets. Histology is of undifferentiated spindle cell sarcoma, often with myofibroblastic, osteosarcomatous or other heterologous elements.

Growth pattern. Intraluminal growth with obstruction, extension through the vessel wall into mediastinum, lung and heart, and tumour embolisation to lung, brain, bone and other organs.

Behaviour. Median survival is about 1.5 months without treatment, about 12 to 18 months with surgery and a few months longer with multimodal therapy. Complete resection (R0) is the strongest predictor of survival, and local recurrence is frequent.

• Pulmonary artery tumours: progressive dyspnoea, cough, chest pain, haemoptysis, fever, weight loss and anaemia. Signs of pulmonary hypertension and right heart failure.
• Aortic tumours: embolic events (limb ischaemia, stroke), claudication, hypertension and abdominal pain.
• Clinical clues for sarcoma instead of thromboembolism: symptoms over weeks to months, weight loss, fever, anaemia, raised inflammatory markers, unilateral central filling defect and no response to anticoagulation.

Red flags.

• Syncope, right heart failure or haemodynamic instability.
• Massive haemoptysis.
• Embolic stroke or acute limb ischaemia.
• Progression of a presumed thromboembolism on adequate anticoagulation.

• CT pulmonary angiography: unilateral, central, expansile filling defect with lobulated margins that may extend beyond the vessel wall, and heterogeneous enhancement, with no distal tapering typical of chronic thrombus. CT aortography for aortic tumours.
• MRI: enhancement of the intraluminal mass (thrombus does not enhance).
• FDG-PET: high uptake (SUVmax over about 3.5), unlike bland thrombus.
• Echocardiography for right ventricular function and cardiac extension.
• Tissue diagnosis through endovascular catheter biopsy, transthoracic or transbronchial biopsy, or at surgery. Immunohistochemistry: MDM2 and CDK4 positive, with smooth muscle and endothelial markers negative to exclude other sarcomas. FISH for MDM2 amplification.
• Staging: CT chest, abdomen and pelvis, MRI brain and bone scan or PET.

Differential diagnosis.

• Acute and chronic pulmonary thromboembolism
• Tumour thrombus (renal cell carcinoma, hepatocellular carcinoma, adrenal tumour)
• Takayasu arteritis and other large vessel vasculitis
• Cardiac myxoma and other cardiac tumours
• Angiosarcoma, leiomyosarcoma and fibrosarcoma of vessels
• Mediastinal tumour invading vessels
• Fibrosing mediastinitis

Management is by a multidisciplinary team with cardiothoracic, vascular and sarcoma expertise. Thrombolysis is not given when sarcoma is suspected.

Surgery.

• Pulmonary artery tumours: pulmonary endarterectomy or resection with reconstruction, or pneumonectomy, on cardiopulmonary bypass, aiming at complete resection.
• Aortic tumours: resection with graft replacement.
• Palliative debulking can relieve obstruction in selected patients.

Radiotherapy. Preoperative or adjuvant 50 to 60 Gy in 25 to 30 fractions where the field allows, with attention to cardiac and lung tolerance.

Chemotherapy. Evidence is retrospective. Adjuvant or palliative anthracycline based therapy is used.

• Doxorubicin: 75 mg/m2 IV every 3 weeks for up to 6 cycles; maximum cumulative working ceiling 450 mg/m2; monitoring: echocardiography at baseline and every 2 cycles, FBC before each cycle; adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid; consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Doxorubicin with ifosfamide: doxorubicin 75 mg/m2 total each cycle (25 mg/m2 daily on days 1 to 3) with ifosfamide 10 g/m2 total (2.5 g/m2 daily on days 1 to 4) IV, with mesna at a total of 60% to 100% of the ifosfamide dose and pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy, every 3 weeks for up to 6 cycles; maximum doxorubicin cumulative working ceiling 450 mg/m2 and ifosfamide 10 g/m2 each cycle; monitoring: FBC, creatinine, urinalysis for haematuria, neurological status (ifosfamide encephalopathy), echocardiography; adjustment: avoid ifosfamide when eGFR is under 30 mL/min/1.73 m2 and reduce by about 25% to 50% when it is 30 to 59, stop for grade 2 neurotoxicity, reduce doxorubicin for hepatic impairment (bilirubin 20 to 51 micromol/L by 50%, 53 to 85 micromol/L by 75%, over 85 micromol/L avoid).
• Right ventricular failure needs optimisation before chemotherapy, and anthracycline is used with caution.

Palliative care. Early referral for dyspnoea, pain and anxiety.

Monitoring. CT of the chest every 3 months for 2 years, then 6 monthly, with MRI brain at 6 monthly intervals in the first 2 years.

Referral and escalation.

• Urgent cardiothoracic and sarcoma referral when a central filling defect shows features of tumour or fails to respond to anticoagulation.
• Same day admission for syncope, right heart failure or major haemoptysis.

Special groups.

• Pregnancy: extremely rare. Urgent multidisciplinary review.
• Misdiagnosis as chronic thromboembolic disease is common, so histology is obtained before endarterectomy when feasible.
• Anticoagulation does not treat the tumour. Stop it when sarcoma is confirmed unless another indication exists.