Liver Angiosarcoma

Etiology

Around 75% of tumors have no known etiology, but the most common known etiologic factors are exposure to vinyl chloride monomer and other industrial materials, iatrogenic exposure to colloidal thorium dioxide (Thorotrast), androgenic corticosteroid use, chronic arsenic ingestion, and exposure to radium. Results from studies have also shown an association between liver cancer and exposure to diethylstilbestrol, urethane, cyclophosphamide, and oral contraceptives. Hepatic angiosarcoma due to environmental exposure has a prolonged latency period of 10 to 40 years.

Vinyl chloride was formerly used to produce polyvinyl chloride. In 1949, it was recognized that the highly reactive epoxide chloroethylene oxide produced during the reaction caused hepatorenal damage. The latency period is about 20 years. Results from large database studies have shown that 12.8% of patients with liver angiosarcoma had a history of vinyl chloride exposure.[5] Cancer associated with vinyl chloride monomer exposure is associated with TP53 mutations. 

Thorotrast was used as a radiocontrast material, but its use was stopped shortly thereafter following several reports of organ damage and fatalities. In the liver, the substance is taken up and stored by Kupffer cells, and after cellular destruction, it is stored in the periportal area. This results in periportal, periacinar, and Glisson capsule fibrosis. Kirsten rat sarcoma viral oncogene homolog (KRAS2) mutations have been found in cancer cells from individuals exposed to Thorotrast. Chronic arsenic intoxication initially results in hepatomegaly followed by the development of steatosis, cell necrosis, fibrosis, and cirrhosis.[2][6][7][8]

Epidemiology

Hepatic angiosarcoma accounts for 0.1% to 2% of all primary hepatic malignant neoplasms, but it is still considered the third most common primary hepatic malignant neoplasm. The condition usually occurs in older men, with a peak incidence in the sixth or seventh decade of life. Men are more frequently affected than women, with a ratio of 3:1 to 4:1. However, in childhood, incidence is higher in girls than in boys. Results from studies have shown an increase in the incidence of all angiosarcomas, including hepatic angiosarcoma, in the last 2 decades.[2][5][9][10][11]

Pathophysiology

Hepatic angiosarcoma is primarily composed of vascular or lymphatic endothelial cells and abundant vasculature. Spindle or pleomorphic cells line or grow into the lumina of preexisting vascular spaces, including sinusoids and terminal hepatic venules, causing hepatocyte atrophy and forming vascular channels. Hepatic angiosarcoma can sometimes form solid tumor masses. Hepatic angiosarcoma should be considered when a hepatic bleeding mass is encountered. Metastatic spread usually occurs to the lungs and hilar lymph nodes, but can also spread to the spleen and bones.[2][3][12]

Histopathology

Histologically, the malignant neoplasm is composed of spindle-shaped and polyhedral cells, exhibiting various vascular channel patterns. Solid areas that resemble fibrosarcoma and polynuclear giant cells may also be seen. Tumor invasion of the portal and hepatic vein branches is common. Areas of infarct, atrophy, and fibrosis are also commonly seen because parenchymal loss causes scarring and occlusion of preexisting vessels. Immunohistochemical markers, including CD31, CD34, ETS-related gene (ERG), Ulex europaeus agglutinin I, and factor VIII–related antigen, can aid diagnosis. Because of the highly vascular nature of the tumor, liver biopsy has a high risk of morbidity and mortality.[2][12][13][14][15]

History and Physical

Hepatic angiosarcoma usually presents with nonspecific symptoms, including right upper quadrant abdominal pain, weight loss, abdominal distention, jaundice, and fatigue.[2] The physical examination can reveal jaundice, ascites, and hepatomegaly.[14] However, most patients are asymptomatic early in the disease course, and the lesions are found incidentally on imaging. Hepatic angiosarcoma is often diagnosed at an advanced stage, with distant metastasis present in over 60% of patients at presentation. The most common sites of metastases are the lung and hilar lymph nodes, followed by the spleen and bones.[15]

Evaluation

Diagnosing hepatic angiosarcoma is challenging because of nonspecific symptoms. Most liver tumors are detected incidentally on abdominal imaging. Differentiating hepatic angiosarcoma from other hepatic tumors is difficult because of its hypervascularity. Ultrasonography may reveal multiple nodules or a solitary mass with variable echogenicity resulting from necrosis or hemorrhage. Computed tomography and MRI are commonly used for detection. On unenhanced CT, lesions typically appear hypodense, with occasional hyperdense areas due to hemorrhage. (see Image. Hepatic Angiosarcoma). MRI highlights the hemorrhagic, heterogeneous, and hypervascular features of these lesions. Multiphasic contrast-enhanced CT and MRI are the preferred imaging modalities for hepatic angiosarcoma because they best demonstrate tumor vascularity. During contrast administration, these tumors show progressive, heterogeneous enhancement in the delayed phase, with a centripetal or diffuse flash-fill pattern, without rapid contrast washout, which helps distinguish them from hepatocellular carcinoma or hypervascular metastases.[16]

Laboratory studies often reveal elevated alanine aminotransferase and aspartate aminotransferase levels, indicating hepatocellular injury and tumor replacement of normal liver tissue. Anemia and thrombocytopenia are also common due to the consumption of clotting factors. Tumor markers such as α-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19-9, and cancer antigen 125 are typically normal or only slightly elevated. Definitive diagnosis requires correlation of radiological findings with histological interpretation. Despite an accurate diagnosis, the tumor often progresses rapidly and is associated with a poor prognosis.[2][3][4][8][12][17]

Treatment / Management

Primary hepatic angiosarcoma has an aggressive clinical course with an extremely poor prognosis, with results from studies showing a 1-year survival rate of 12.8%.[5] Complete hepatic resection is the only potentially curative treatment. Results from studies have shown improved survival, particularly when the lesion is limited to a single lobe and distant metastases are absent. However, surgical procedures are associated with high rates of postoperative complications, mortality, and recurrence. Liver transplant is generally not recommended because of rapid disease progression and high recurrence rates, with posttransplant survival less than 7 months.[17][18]

Most cases are diagnosed at an advanced, unresectable stage, although results from some case reports have shown benefits from chemotherapy. Although no standardized regimen exists, agents such as paclitaxel, gemcitabine, docetaxel, doxorubicin, and cyclophosphamide have been used sparingly. Evidence suggests increased survival with chemotherapy, and adjuvant chemotherapy after resection may also provide benefit.[1][15]

Transarterial chemoembolization and other local therapies are used for unresectable liver-dominant disease and for controlling bleeding in cases of tumor rupture. Transarterial chemoembolization may be used alone or in combination with other modalities and may improve survival in select cases.[15][19] Because hepatic angiosarcoma is rare, most available data are limited to small case series and retrospective studies, and no established guidelines for optimal treatment exist. Treatment should be individualized and coordinated through an interdisciplinary team, and referral to a sarcoma specialty center is recommended by the American College of Gastroenterology.[1][18][16][20][21](B2)

Differential Diagnosis

Differential diagnoses of hepatic angiosarcoma include the following:

• Inflammatory disorders of the liver
• Benign vascular diseases of the liver
• Kaposi sarcoma
• Liver metastasis from angiosarcoma arising in other organs
• Epithelioid hemangioendothelioma
• Hepatocellular carcinoma
• Fibrosarcoma [2]

Staging

Clinical staging of angiosarcoma is based on the American Joint Committee on Cancer staging system for soft tissue sarcoma, which considers tumor size, depth, regional lymph node involvement, distant metastases, and histological grade. All hepatic angiosarcomas are considered deep tumors because they are located beneath the superficial fascia. Stage II and III hepatic angiosarcomas are rare, making outcomes more difficult to predict. Results from studies have shown that the majority of cases are stage I or IV.[21]

Prognosis

Hepatic angiosarcoma is a rapidly progressive malignant neoplasm, and most patients die within 6 months, with only 5% to 11% of patients surviving 5 years. Tumor rupture is a particularly poor prognostic event, often resulting in death within 1 month. Factors associated with poor prognosis include male sex, older age, and advanced stage at diagnosis. Surgical procedures and chemotherapy have been shown to increase survival from 1 month with no treatment to 6 months.[2][3][5][22][5][3]

Complications

Hepatic angiosarcoma is a rapidly fatal tumor, with mortality within 6 months from liver failure or hemorrhage. Tumor rupture may occur, resulting in hemoperitoneum, which is seen in 17% to 27% of cases. Once tumor rupture occurs, transarterial embolization is usually the first intervention performed to stabilize the patient and stop the bleeding. However, no definitive recommendation exists for treating acute bleeding from liver angiosarcoma because of the rarity of the tumor.[2][4][13] Other rare complications include Kasabach-Merritt syndrome, characterized by thrombocytopenia and hyperconsumption of coagulation factors within a vascular tumor, and disseminated intravascular coagulation.[15]