Leiomyosarcoma of the Inferior Vena Cava

Leiomyosarcoma of the inferior vena cava (IVC) is a malignant smooth muscle tumour arising from the wall of the IVC. It is the commonest primary malignant tumour of the IVC, and complete surgical resection is the only curative treatment.

It is very rare. Women are affected about four times as often as men, with a median age in the 50s to 60s. Tumours arise in the lower (infrarenal), middle (renal to hepatic veins) and upper (hepatic veins to right atrium) segments, with the middle segment commonest.

No predisposing cause is established.

Pathophysiology. Tumours grow intraluminally, extraluminally or in both directions. Smooth muscle actin, desmin and h-caldesmon are positive. Complex karyotype with TP53, RB1 and PTEN alterations is typical.

Grade. Low to high grade by differentiation, necrosis and mitotic count, with grade 3 tumours having the worst outcome.

Behaviour. Growth is slow, and symptoms depend on the segment involved. Metastasis occurs in 30% to 50% (liver, lung), and local recurrence in 30% to 50%. Five year survival is about 40% to 60% after complete resection and under 10% without it.

• Abdominal or back pain, a palpable abdominal mass, weight loss and fatigue.
• Lower segment: leg oedema, varicose veins and venous claudication.
• Middle segment: flank pain, haematuria, nephrotic range proteinuria, renal impairment and hypertension from renal vein involvement.
• Upper segment: Budd-Chiari syndrome (hepatomegaly, ascites, jaundice, abdominal pain), and with cardiac extension dyspnoea, syncope and signs of right sided obstruction.

Red flags.

• Acute Budd-Chiari syndrome with rising bilirubin, coagulopathy or encephalopathy.
• Pulmonary embolism from tumour embolisation.
• Rapidly progressive renal failure or anuria.
• Right atrial extension with syncope.

• Duplex ultrasound for a first look. Contrast CT or MRI venography to define the segment, intraluminal enhancement (bland thrombus does not enhance), extraluminal component, renal and hepatic vein involvement, and invasion of adjacent organs.
• Echocardiography for atrial extension.
• Percutaneous core biopsy of the extraluminal component or a distant lesion, with smooth muscle immunohistochemistry.
• Staging: CT chest, abdomen and pelvis (liver and lung), with MRI liver if needed.
• Split renal function (renal scintigraphy), creatinine, liver tests, coagulation, echocardiography and cardiac assessment before surgery.

Differential diagnosis.

• Bland IVC thrombosis
• Tumour thrombus from renal cell carcinoma, adrenal cortical carcinoma or hepatocellular carcinoma
• Intravenous leiomyomatosis (benign, from uterine fibroids)
• Retroperitoneal leiomyosarcoma invading the IVC
• Angiosarcoma and other vascular sarcomas
• Lymphoma and retroperitoneal fibrosis
• Congenital IVC anomaly

Surgery. Complete resection with negative margins by a team with vascular, hepatobiliary and cardiac skills.

• Lower segment: resection with ligation is often tolerated because of collateral flow, and compression stockings are used.
• Middle segment: resection with IVC reconstruction (prosthetic graft such as PTFE), with right nephrectomy or renal vein reimplantation when the renal veins are involved.
• Upper segment: resection with hepatic vascular exclusion, and cardiopulmonary bypass when the tumour extends into the right atrium.
• Perioperative anticoagulation after reconstruction, with the agent and duration set by the vascular team.

Radiotherapy. Preoperative or postoperative 50 Gy in 25 fractions to lower local recurrence, particularly for close or positive margins.

Chemotherapy. Not routine as adjuvant therapy. For unresectable or metastatic disease:

• 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.
• Gemcitabine with docetaxel: gemcitabine 900 mg/m2 IV over 90 minutes on days 1 and 8 with docetaxel 75 mg/m2 IV on day 8, with pegfilgrastim 6 mg subcutaneously on day 9, every 21 days until progression; maximum gemcitabine 900 mg/m2 and docetaxel 75 mg/m2 each cycle; monitoring: FBC before each dose, liver tests, creatinine, pneumonitis, oedema; adjustment: do not give docetaxel when bilirubin exceeds the upper limit or AST or ALT exceeds 1.5 times the upper limit with alkaline phosphatase over 2.5 times, reduce both agents by 25% for grade 3 to 4 toxicity, caution when creatinine clearance is under 30 mL/min.
• Trabectedin (after anthracycline): 1.5 mg/m2 IV over 24 hours through a central line every 3 weeks until progression or intolerance; maximum 1.5 mg/m2 each cycle; monitoring: ALT, AST, bilirubin, alkaline phosphatase and creatine kinase before each cycle, FBC, LVEF at baseline and every 2 to 3 months; premedication with dexamethasone 20 mg IV 30 minutes before; adjustment: do not give when bilirubin exceeds the upper limit, hold for ALT or AST over 2.5 times the upper limit or creatine kinase over 5 times, reduce to 0.9 mg/m2 in moderate hepatic impairment, not studied when creatinine clearance is under 30 mL/min.
• Resection of isolated liver or lung metastases in selected patients.

Monitoring. CT or MRI every 3 to 4 months for 2 years, then 6 monthly to year 5, then annually. Duplex ultrasound for graft patency, and renal and liver function tests at each visit.

Referral and escalation.

• Referral to a sarcoma centre with vascular, hepatobiliary and cardiac surgical capability before any biopsy or surgery.
• Same day admission for acute Budd-Chiari syndrome, pulmonary embolism or acute kidney injury.

Special groups.

• Renal impairment: nephrectomy is weighed against residual function, and chemotherapy doses are adjusted.
• Pregnancy: urgent multidisciplinary review, and defer chemotherapy and radiotherapy.
• Older adults and those with cardiac disease: assess operative risk, and prefer lower segment resection when oncologically suitable.