Epithelioid Haemangioendothelioma

Epithelioid haemangioendothelioma is a rare vascular neoplasm of intermediate to malignant behaviour, characterised by WWTR1::CAMTA1 fusion in about 90% and YAP1::TFE3 fusion in about 10%. Epithelioid endothelial cells lie in a myxohyaline stroma, and disease is often multifocal.

Incidence is under 1 case in 1,000,000 people each year. Median age is 30 to 50, with a female predominance in hepatic disease. Sites are the liver, lung, bone and soft tissue, and a minority involve pleura or peritoneum.

Associations in hepatic cases are oral contraceptives, vinyl chloride, liver trauma and viral hepatitis, though most are sporadic.

Pathophysiology. The fusions activate the Hippo signalling effectors TAZ and YAP, and CAMTA1 nuclear staining identifies the CAMTA1 fusion. Vascular markers (CD31, CD34, ERG) are positive.

Prognostic features. 3 or more mitoses in 50 high power fields, size over 3 cm and spindle cell morphology predict aggressive behaviour. YAP1::TFE3 tumours are more often solitary, with vasoformative features.

Behaviour. The course is highly variable: stable for many years or rapidly progressive. Five year survival is about 60% to 80%, and median survival with hepatic disease is 5 to 10 years or longer. Serosal involvement (pleural effusion, bloody ascites) predicts a poor outcome.

• Hepatic: abdominal pain, hepatomegaly, weight loss, abnormal liver tests (cholestatic), and Budd-Chiari syndrome. Many are asymptomatic.
• Pulmonary: multiple small nodules, cough, dyspnoea, haemoptysis, haemorrhagic pleural effusion. Many are asymptomatic.
• Bone: pain, pathological fracture. Soft tissue: painless mass.
• Fatigue, fever and weight loss with progression.

• Liver imaging (CT and MRI): multiple peripheral nodules that coalesce, capsular retraction, a halo or target pattern and a lollipop sign (vessel ending in a nodule). Lung: bilateral, small, well defined nodules, with calcification in some.
• Biopsy (percutaneous liver biopsy with caution for bleeding). CAMTA1 nuclear immunohistochemistry is sensitive and specific, with TFE3 staining and FISH or RT-PCR for the variant.
• Staging with CT chest, abdomen and pelvis, bone scan or FDG-PET (variable uptake), and MRI brain only for symptoms.
• Baseline liver tests, coagulation, FBC, creatinine and albumin.

Differential diagnosis.

• Angiosarcoma (high grade, aggressive)
• Haemangioma and other benign vascular lesions
• Hepatic metastases, hepatocellular carcinoma and cholangiocarcinoma
• Pulmonary metastases, sarcoidosis and granulomatous infection
• Pleural mesothelioma
• Kaposi sarcoma and pseudomyogenic haemangioendothelioma

Treatment is individualised by the pace of disease.

Observation. Asymptomatic, indolent disease (including lung nodules and limited liver lesions) is observed with imaging every 3 to 6 months. Treatment starts for symptoms or documented progression.

Surgery and local therapy.

• Resection for localised disease, or ablation or embolisation for selected liver lesions.
• Liver transplantation for unresectable hepatic disease, even with limited extrahepatic disease, with 5-year survival of about 80%. Referral to a transplant centre is early.

Systemic therapy for progressive or symptomatic disease.

• Sirolimus: starting dose 2 mg orally once daily, adjusted to a trough of 5 to 15 ng/mL, until progression or intolerance; maximum set by trough level (usually 2 to 6 mg daily); monitoring: trough level at 5 to 7 days after each change, lipids, glucose, creatinine and urine protein, FBC, infection, pneumonitis and mouth ulcers; adjustment: reduce the dose in hepatic impairment (about one third to one half), avoid strong CYP3A4 and P-glycoprotein inhibitors and inducers, no routine renal adjustment, avoid grapefruit.
• Pazopanib: 800 mg orally once daily on an empty stomach until progression; maximum 800 mg daily; monitoring: liver tests at baseline, weeks 3, 5, 7 and 9, then months 3 and 4 and as needed, blood pressure at each visit, ECG and electrolytes, thyroid function, proteinuria; adjustment: reduce in 200 mg steps for toxicity, 200 mg daily in moderate hepatic impairment (bilirubin over 1.5 to 3 times the upper limit), avoid in severe impairment, stop for ALT over 8 times the upper limit, avoid strong CYP3A4 inhibitors.
• Cytotoxic regimens (carboplatin with paclitaxel, anthracycline based therapy) have been used for rapidly progressive disease, with modest benefit. Interferon alfa, thalidomide and bevacizumab have case level evidence.
• Radiotherapy for painful bone lesions.

Monitoring. CT or MRI every 3 to 6 months. Liver tests every 3 months with hepatic disease.

Referral and escalation.

• Sarcoma and hepatobiliary or transplant multidisciplinary review at diagnosis.
• Urgent admission for haemoptysis, Budd-Chiari syndrome, tense ascites or pleural effusion with respiratory compromise.

Special groups.

• Women taking oestrogen containing contraception: stop it at diagnosis.
• Pregnancy: tumours may grow with oestrogen exposure. Avoid sirolimus and pazopanib.
• Hepatic impairment: adjust sirolimus and pazopanib doses.