Continuing Education Activity

Angiosarcoma is described as a high-grade, malignant neoplasm of endothelial cells of blood or lymphatic vessels. Primary hepatic angiosarcoma is a rare but aggressive malignancy and the most common primary malignant mesenchymal tumor of the liver in adults. This activity examines when this condition should be considered on differential diagnosis and how to properly evaluate it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Describe the various radiological studies used for the evaluation of hepatic angiosarcoma.
• Review the pathophysiology of liver angiosarcoma.
• Outline etiological factors predisposing to liver angiosarcoma.
• Summarize the importance of collaboration and communication among the interprofessional team to enhance the delivery of care for the patients affected by angiosarcoma.

Introduction

Angiosarcoma is described as a high-grade, malignant neoplasm of endothelial cells of blood or lymphatic vessels. It occurs most commonly in the head and neck, followed by the breast but the liver is the fifth most common site of angiosarcomas. Primary hepatic angiosarcoma is a rare but aggressive malignancy and is the most common primary malignant mesenchymal tumor of the liver in adults. [1][2][3]

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 steroid use, chronic arsenic ingestion, and exposure to radium. There have also been studies showing an association between cancer and exposure to diethylstilbestrol, urethane, cyclophosphamide, and oral contraceptives. Hepatic angiosarcoma due to environmental exposure has a prolonged latency period of 10-40 years. 

Vinyl chloride was formerly used in the production of polyvinyl chloride. It was recognized in 1949 that the highly reactive epoxide chloroethylene oxide produced during the reaction caused hepatorenal damage. The latency period is about 20 years. Cancer-associated with vinyl chloride monomer exposure has been found to have TP53 mutations.

Thorotrast was used as a radiocontrast material, but its use was stopped shortly after following several reports of organ damage and fatalities. In the liver, the substance is taken up and stored by Kupffer cells and then gets stored in the periportal area after its destruction. This results in periportal, periacinar, and Glisson’s capsule fibrosis. KRAS-2 mutations have been found in cancer cells from thorotrast exposure.

Chronic arsenic intoxication initially results in hepatomegaly followed by the development of steatosis, cell necrosis, fibrosis, and cirrhosis. [1][4][5][6]

Epidemiology

Hepatic angiosarcoma accounts for 0.1%-2% of all primary hepatic malignancies, but it is still considered to be the third most common primary hepatic malignancy. It usually occurs in older men with a peak incidence in the sixth or seventh decade of life. Males are more frequently affected than females with a ratio of 3-4:1. However, in childhood, there is a higher incidence amongst girls compared to boys.[1][7][8]

Pathophysiology

Hepatic angiosarcoma is primarily made up of vessels or lymphatic endothelial cells, so it is composed of abundant vasculature. Spindle or pleomorphic cells line or grow into the lumina of preexisting vascular spaced like sinusoids and terminal hepatic venules, causing hepatocyte atrophy and formation of vascular channels. It can sometimes form into solid masses of a tumor. Hepatic angiosarcoma should be considered when a hepatic bleeding mass is encountered. Metastatic spread usually occurs in the lungs and hilar lymph nodes but can also spread to the spleen and bones. [1][2][9]

Histopathology

Histologically, the malignancy is composed of spindle-shaped and polyhedral cells, demonstrating various patterns of vascular channels. Solid areas that resemble fibrosarcoma and polynuclear giant cells may also be seen. It is common to see tumor invasion of a portal and hepatic vein branches. Areas of infarct, atrophy, and fibrosis are also commonly seen as parenchymal loss causes scarring and occlusion of pre-existing vessels. CD31, CD34, Ulex europaeus agglutinin I, and factor VIII-related antigen are immunohistochemical markers that can be used to aid diagnosis. Due to the highly vascular nature of the tumor, liver biopsy has a high risk of morbidity and mortality.[1][9][10][11][12]

History and Physical

Hepatic angiosarcoma usually presents with nonspecific symptoms, including right upper quadrant abdominal pain, weight loss, distention, jaundice, and fatigue.[1] The physical examination can reveal jaundice, ascites, and hepatomegaly.[13] They can also be asymptomatic and found incidentally on imaging.

Evaluation

Diagnosing hepatic angiosarcoma remains a challenge due to the nonspecificity of symptoms. Liver tumors are most commonly detected incidentally on abdominal imaging. It is difficult to differentiate hepatic angiosarcoma from other hepatic tumors radiologically due to the hypervascular characteristic of hepatic angiosarcoma. Ultrasonography shows multiple nodules or solitary mass with varying echogenicity from necrosis and hemorrhage in hepatic angiosarcoma lesions. Many studies concluded that contrast-enhanced computed tomography is the best method for the diagnosis of hepatic angiosarcoma. Lesions appear hypodense with multiple patterns of enhancement and postcontrast; the lesions become partly or completely isodense in comparison with the hepatic tissue. MRI can also be used to identify hepatic angiosarcoma as it can reflect the hemorrhagic, heterogeneous, and hypervascular nature of the lesions.

Laboratory studies in patients with hepatic angiosarcoma will show elevated alanine transaminase and aspartate transaminase, as well as thrombocytopenia and anemia, as normal liver parenchyma is replaced by tumor. Tumor markers like AFP, CEA, CA19-9, and CA125 are in the normal range or only slightly elevated. Diagnosis of hepatic angiosarcoma should be made with a correlation of radiological findings and histological interpretation (as described previously). It is important to bear in mind that even with a correct diagnosis, rapid progression of the tumor yields a poor prognosis. [1][2][3][6][9][12]

Treatment / Management

Primary hepatic angiosarcoma has an aggressive clinical course, and the prognosis is poor in inoperable cases. The majority of patients die within six months of diagnosis, and even with treatment, only around 3% of patients live more than two years. Complete hepatic resection or radical resection of the tumor is the most effective form of treatment for single lesions; however, it is not always feasible in metastatic disease. Liver transplant is not recommended in these cases due to the high rate of recurrence and the rapid progression of the disease. Survival after liver transplant is less than seven months. Unfortunately, no effective chemotherapy has been established. There has been one report that showed the efficacy of using 5-FU-carboplatin with doxorubicin or ifosfamide in patients with unresectable hepatic angiosarcoma and distant metastasis. A study with a large patient population showed a significant survival benefit of surgical treatment for stage I hepatic angiosarcoma and the prognosis of patients that underwent surgical treatment were better than patients who received non-operative treatment. Transcatheter arterial chemoembolization (TACE) can also be used with palliative intention or to control bleeding. Unfortunately, there are no established guidelines on optimal treatment modalities regarding surgery, chemotherapy, and radiation, as there are different outcomes that have been studied. [10][14][11][15]

Differential Diagnosis

Differential diagnosis of hepatic angiosarcoma include: 

• Inflammatory disorders of the liver
• Benign vascular diseases of the liver
• Kaposi sarcoma
• Liver metastasis from angiosarcoma arising in other organs
• Epitheloid haemangioendothelioma
• Hepatocellular carcinoma
• Fibrosarcoma [1]

Staging

Clinical staging of angiosarcoma is based on the American Joint Committee on Cancer Staging System for soft tissue sarcoma - which is based on tumor size, depth, the presence or absence of regional lymph nodes, distant metastases, and histological grade. All hepatic angiosarcomas are considered deep tumors, as they are located beneath the superficial fascia. Stage II and III hepatic angiosarcomas are rare, making their outcomes more difficult to predict. The majority of cases in studies were stage I or IV. [15]

Prognosis

Hepatic angiosarcoma is a rapidly growing and fatal tumor. The majority of patients die within six months of diagnosis from liver failure or hemorrhage, and most die within a year, even after surgical resection. Patients with tumor rupture often die within one month. [1][2]

Complications

It is a rapidly fatal tumor with mortality within six months from liver failure or hemorrhage. Tumor rupture may occur and result in hemoperitoneum. Once this happens, transarterial embolization is usually the first intervention done to stabilize the patient and stop the bleed. However, there is no definite recommendation on treating acute bleeding of liver angiosarcoma due to the rarity of the tumor. Some patients have also been reported to develop features of disseminated intravascular coagulation. [3][1][12]

Deterrence and Patient Education

The diagnosis of hepatic angiosarcoma remains difficult during the early stages due to unspecific symptoms. Prognosis is poor due to its rapid progression, high recurrence rate, and resistance to traditional chemotherapy and radiotherapy. Surgical resection remains the most definite curative therapy. However, there are no therapeutic guidelines established to date due to the rarity of cancer. Exposure to environmental and chemical substances, as previously mentioned, remains the most common known etiology of the disease. [1][3]

Enhancing Healthcare Team Outcomes

Unfortunately, due to the small number of cases of this rare malignancy, therapeutic guidelines have not been definitively established. Diagnosing hepatic angiosarcoma remains a challenge due to the nonspecificity of presenting symptoms such as weight loss and abdominal pain. Laboratory cancer markers are also non-specific to the diagnosis and diagnosing the tumor on radiological imaging is difficult. Biopsy of the lesion carries risks of bleeding due to the highly vascular nature of cancer. A collaborative effort must be made between an interprofessional team of primary care doctors, hepatologists, radiologists, and pathologists in making a diagnosis. Once a diagnosis of hepatic angiosarcoma is made, prognosis remains very poor, and treatment would include surgery versus palliative care. Surgeons, oncologists, and palliative care providers must get involved at this point to determine the best course of action based on the patient’s wishes and prognosis [Level IV]. [15] Specialty care nurses in oncology and hospice assist in care, monitoring patients, providing education to patients, and updating the team on patient status. [Level 5]