Vinyl Chloride-Associated Angiosarcoma

Vinyl chloride associated angiosarcoma is a malignant vascular tumour of the liver caused by long term exposure to vinyl chloride monomer. It is the signature tumour of this exposure, grows aggressively and has a poor outlook.

Epidemiology. Hepatic angiosarcoma is rare. Vinyl chloride is the best defined cause. Other causes are arsenic, thorium dioxide contrast (no longer used) and androgenic anabolic steroids, and most current cases have no identified cause.

Exposure. Reactor cleaning and polymerisation in polyvinyl chloride plants, mainly before exposure limits were tightened.

Latency. Usually 15 to 30 years from first exposure, rising with cumulative dose. Cases appear after exposure has ended.

Prognosis. Median survival is about 6 months overall. Longer survival follows only complete resection, and few tumours are resectable at diagnosis.

Pathophysiology.

Vinyl chloride is converted by CYP2E1 to chloroethylene oxide and chloroacetaldehyde, which form promutagenic DNA adducts in sinusoidal endothelial cells.

Characteristic mutations affect KRAS (codon 13) and TP53. Tumour growth along sinusoids causes haemorrhage and peliosis like change.

• Abdominal pain, weight loss, fatigue, hepatomegaly and ascites, often with several months of symptoms.
• Anaemia, thrombocytopenia and disseminated intravascular coagulation.
• Spread to spleen, lung and bone.

Red flags.

• Sudden severe abdominal pain with hypotension (tumour rupture and haemoperitoneum).
• Haematemesis or melaena.

• Exposure history with duration, reactor cleaning and latency.
• Ultrasound shows a heterogeneous mass or multiple nodules. Contrast CT or MRI shows peripheral nodular enhancement with variable filling, and haemorrhage within lesions.
• Alpha fetoprotein is usually normal, which helps separate it from hepatocellular carcinoma.
• Liver tests, full blood count, coagulation screen and fibrinogen.
• Biopsy carries a high bleeding risk and is directed by a specialist hepatobiliary team. Histology shows atypical endothelial cells lining sinusoids, positive for CD31, CD34 and ERG, and negative for cytokeratins.
• Staging with CT of chest and abdomen.

Differential diagnosis. Hepatocellular carcinoma, epithelioid haemangioendothelioma, cholangiocarcinoma, metastases, haemangioma, peliosis hepatis, hepatic abscess.

• Multidisciplinary hepatobiliary and sarcoma team review at diagnosis.
• Complete resection for the rare localised tumour. Liver transplantation is not advised because of early recurrence.
• Paclitaxel 80 mg/m2 intravenously over 1 hour on days 1, 8 and 15 of each 28-day cycle, until progression or intolerance. Premedicate with dexamethasone 10 mg, chlorphenamine 10 mg and famotidine 20 mg intravenously. Maximum 80 mg/m2 each dose. Monitor full blood count before each dose (hold for neutrophils under 1.0 x 10^9/L or platelets under 100 x 10^9/L), neuropathy and hypersensitivity. Reduce dose by 25% in mild and 50% in moderate hepatic impairment and avoid in severe impairment; no renal adjustment. Evidence derives from small series and soft tissue sarcoma data.
• Doxorubicin 60 mg/m2 intravenously every 21 days for up to 6 cycles, as an alternative. Maximum cumulative dose 450 to 550 mg/m2. Monitor echocardiography before treatment and at cumulative doses over 300 mg/m2, plus blood counts. Reduce by 50% when bilirubin is 20 to 50 micromol/L, by 75% when 51 to 85 micromol/L, and avoid when over 85 micromol/L. Avoid in significant cardiac disease and pregnancy.
• Haemorrhage or rupture: resuscitation, transfusion and arterial embolisation by interventional radiology.
• Palliative care involvement early.

Monitoring. Imaging every 2 to 3 cycles; blood counts, liver function and coagulation at each cycle.

Referral and escalation. Hepatobiliary surgery, oncology and palliative care at diagnosis; emergency admission for rupture; occupational physician for exposure review and surveillance of co-workers (ultrasound every 6 to 12 months for those with fibrosis); notification and compensation where required.