Hepatic angiosarcoma

Primary hepatic angiosarcoma, Liver angiosarcoma, Angiosarcoma of the liver, PHA

Hepatic angiosarcoma is a rare but highly aggressive cancer that develops in the blood vessels of the liver. Though it accounts for less than 2% of all liver cancers, it is the third most common primary liver cancer and the most common malignant tumor arising from the liver’s blood vessels in adults.

Table of contents

• What is hepatic angiosarcoma?
• How common is this condition?
• Causes and risk factors
• Signs and symptoms
• Serious complications
• Diagnosis
• Treatment approaches
• What to expect

What is hepatic angiosarcoma?

Hepatic angiosarcoma is a type of cancer that begins in the endothelial cells — the cells that line the inside of blood vessels in the liver^[1]. While the most common locations for angiosarcoma are the head and neck, followed by the breast, the liver is the fifth most common site for this type of cancer^[1].

This cancer is classified as a high-grade, malignant tumor, meaning it grows and spreads quickly^[1]. Despite being rare, hepatic angiosarcoma is the most common primary malignant mesenchymal tumor (a cancer arising from connective tissue) of the liver in adults^[1].

• Liver
• Blood vessels

How common is this condition?

Hepatic angiosarcoma is very rare. It accounts for only 0.1% to 2% of all primary liver cancers^[1][2]. Each year, approximately 200 new cases are diagnosed worldwide, with only about 1 person per million developing this condition in the United States^[4].

The disease typically affects older adults, with most cases occurring in people in their 60s or 70s^[1][2]. Men are more frequently affected than women, with a ratio of 3 to 4 males for every female diagnosed^[1]. Interestingly, in children, the disease is more common among girls than boys^[1].

Causes and risk factors

In approximately 75% of cases, the exact cause of hepatic angiosarcoma remains unknown^[1][4]. However, several risk factors have been identified that increase the likelihood of developing this cancer. It’s important to understand that having a risk factor doesn’t mean you will definitely develop the disease — it simply means your risk is higher than average.

Known risk factors include:

Chemical exposures are among the most well-documented risk factors. Exposure to vinyl chloride monomer, which was formerly used in the production of polyvinyl chloride plastic, is a significant risk factor^[1][2]. This highly reactive substance causes liver and kidney damage, and cancers associated with vinyl chloride exposure often have mutations in a gene called TP53^[1].

Chronic arsenic ingestion is another known cause. Long-term arsenic exposure initially results in an enlarged liver, followed by the development of fat accumulation, cell death, fibrosis (scarring), and eventually cirrhosis (late-stage liver scarring)^[1].

Medical exposures also contribute to risk. Thorotrast, a radioactive contrast material used in medical imaging until it was discontinued due to organ damage and fatalities, is associated with hepatic angiosarcoma^[1]. In the liver, Kupffer cells (specialized immune cells) take up and store this substance, leading to scarring around the portal areas of the liver. Cancers from Thorotrast exposure often show mutations in the KRAS-2 gene^[1].

Other medical risk factors include androgenic steroid use, previous radiation therapy, and exposure to certain medications including cyclophosphamide, diethylstilbestrol, urethane, and oral contraceptives^[1][4].

Other associations include exposure to radium and certain genetic syndromes such as neurofibromatosis^[4]. The condition is also associated with hemochromatosis (iron overload in the body)^[4].

An important characteristic of hepatic angiosarcoma related to environmental exposure is its prolonged latency period — the time between exposure and cancer development. This period can range from 10 to 40 years, with vinyl chloride exposure typically showing a latency of about 20 years^[1][2].

Signs and symptoms

One of the challenges in diagnosing hepatic angiosarcoma is that symptoms are often vague, nonspecific, and can easily be mistaken for other conditions^[2][4]. In some cases, particularly in early stages, people may have no symptoms at all, and the cancer is discovered accidentally during medical imaging for other reasons^[2][4].

When symptoms do occur, they may include:

• Pain in the upper right part of the abdomen (the most common symptom, occurring in about 60% of patients)^[4]
• Abdominal distension or bloating (also occurs in about 60% of patients)^[2][4]
• Fatigue or weakness^[2]
• Unexplained weight loss^[2][4]
• Jaundice (yellowing of the skin and eyes)^[2]
• Fever, malaise (general feeling of unwellness), loss of appetite, and vomiting^[4]

During a physical examination, a doctor may find an enlarged liver, fluid accumulation in the abdomen (ascites), or jaundice^[4]. An important and somewhat unusual finding is that liver function is generally maintained until the final stages of the disease, which further complicates early diagnosis^[4].

Serious complications

Hepatic angiosarcoma can lead to several life-threatening complications due to its aggressive nature and the vascular (blood vessel-related) characteristics of the tumor.

Spontaneous tumor rupture is one of the most dangerous complications. This occurs when the tumor breaks open, causing severe bleeding inside the abdomen (hemoperitoneum)^[4][6]. This complication is reported in 15% to 27% of patients and can be fatal^[4]. Factors that contribute to tumor rupture include low platelet counts (thrombocytopenia), anemia, and the highly vascular nature of the tumor itself^[4]. Even when emergency procedures such as transcatheter arterial embolization (TAE) are used to stop the bleeding, the prognosis remains very poor, with a median survival of only 23 days following tumor rupture^[4].

Because the spleen is located near the liver and has a similar blood vessel-rich structure, the cancer commonly spreads to the spleen. This can result in splenic rupture, another source of potentially fatal internal bleeding^[4].

Hepatic angiosarcoma may also result in liver failure, a potentially fatal complication where the liver can no longer perform its essential functions^[4]. Additionally, like many cancers, hepatic angiosarcoma can cause disseminated intravascular coagulation (DIC), a serious condition where blood clots form throughout the body’s small blood vessels^[4].

Diagnosis

Diagnosing hepatic angiosarcoma is challenging because there are no specific symptoms or imaging features that definitively identify this cancer^[7][13]. The diagnosis requires careful evaluation using multiple approaches.

Medical imaging

Various imaging techniques are used to detect liver abnormalities, although they cannot definitively diagnose hepatic angiosarcoma. These include ultrasound, computed tomography (CT) scans, and magnetic resonance imaging (MRI)^[1]. However, because hepatic angiosarcoma and other liver tumors, particularly hepatocellular carcinoma, both have high blood vessel content, it can be difficult to distinguish between them on imaging alone^[4].

CT scans may show a hypervascular mass (a tumor with many blood vessels) that may exhibit active bleeding^[6]. In some cases, angiography (imaging of blood vessels using contrast dye) may be performed to visualize blood flow to the tumor^[6].

Laboratory tests

Blood tests may show abnormalities such as elevated white blood cell counts, anemia, low platelet counts, and abnormal liver function tests^[6]. However, common tumor markers such as alpha-fetoprotein (AFP), CEA, and CA 19-9 are typically within normal ranges, which helps distinguish hepatic angiosarcoma from other liver cancers like hepatocellular carcinoma^[6].

Tissue biopsy

The only way to definitively diagnose hepatic angiosarcoma is through a biopsy — removing a small sample of tissue for examination under a microscope^[7][13]. This is in contrast to hepatocellular carcinoma, where diagnosis is often made based on imaging alone without requiring a biopsy^[7].

Pathologists look for CD31, which is considered the most reliable tumor marker for hepatic angiosarcoma^[4]. The microscopic examination reveals malignant cells originating from the endothelial lining of blood vessels^[9].

Treatment approaches

Treatment for hepatic angiosarcoma is challenging, and there is currently no standardized treatment protocol due to the rarity of the disease^[9][14]. Treatment decisions depend on the stage of the cancer, its location, whether it has spread, and the patient’s overall health.

Surgical treatment

Surgical removal of the tumor (hepatic resection) is considered the most effective treatment and the only potentially curative option for hepatic angiosarcoma^[9][14]. The goal is to achieve negative surgical margins, meaning all cancerous tissue is removed with healthy tissue surrounding it^[9].

However, most patients present with advanced disease and are not candidates for surgery^[9][14]. Early diagnosis is therefore crucial for improving the chances of successful surgical treatment^[13].

In cases where tumor rupture occurs, emergency procedures such as transcatheter arterial embolization (TAE) may be performed to stop active bleeding before definitive surgery can be planned^[6].

Radiation therapy

Radiation therapy may be used as an adjuvant treatment, particularly when surgical margins are involved (meaning cancer cells were found at the edge of the removed tissue)^[19]. However, hepatic angiosarcoma is generally considered resistant to traditional radiation therapy^[6].

Chemotherapy

Approximately 71% of patients receive systemic treatment with chemotherapy^[9]. However, hepatic angiosarcoma is typically resistant to traditional chemotherapy^[6]. Despite this, chemotherapy may be used to slow the growth of cancer cells, particularly in patients who are not surgical candidates^[14].

Immunotherapy

Immunotherapy is an emerging treatment option, with about 29% of patients receiving this type of treatment^[9]. Some patients have shown improved survival with immunotherapy combinations such as ipilimumab and nivolumab^[9]. This represents a promising area for future research.

Liver transplantation

Liver transplantation has not been shown to benefit patients with hepatic angiosarcoma^[6], and is not considered a standard treatment option for this condition.

Ongoing surveillance

For patients who undergo successful treatment, ongoing surveillance with regular imaging is essential because the cancer has a high recurrence rate^[19].

What to expect

The prognosis for hepatic angiosarcoma is unfortunately very poor, reflecting its aggressive nature and the difficulty in achieving early diagnosis^[2][9][14].

Most patients die within 6 months of diagnosis^[4]. Studies show that the median overall survival is approximately 6 months, with a range from as little as 0.07 months to 222.6 months in rare cases^[9]. The 1-year survival rate is only about 30%, while 3-year and 5-year survival rates are approximately 8% and 5%, respectively^[4]. In one study, the 2-year and 5-year overall survival were both 38.6%^[9].

The prognosis of hepatic angiosarcoma is significantly worse than that of hepatocellular carcinoma (the most common type of liver cancer). The median survival for hepatic angiosarcoma is 1.9 months compared to 10.3 months for hepatocellular carcinoma^[7].

However, there have been exceptional cases of long-term survival. The longest reported survivor with hepatic angiosarcoma lived for 14 years after diagnosis^[19]. This patient underwent an initial right hemihepatectomy (removal of the right side of the liver), and 10 years later had another surgery to remove a recurrence, followed by radiation therapy. This case demonstrates that early diagnosis, aggressive surgical treatment, and careful ongoing surveillance can, in rare instances, lead to prolonged survival.

Factors that may contribute to poor outcomes include the aggressive nature of the tumor, its high rate of metastasis (spreading to other parts of the body), and the fact that most patients present with advanced disease when treatment options are limited^[9][14].