Hepatic angiosarcoma is an extremely rare and aggressive cancer that develops in the blood vessels of the liver. Despite being uncommon, it ranks as the third most frequent primary liver cancer, affecting mostly older men and carrying one of the poorest survival rates among liver malignancies.

Epidemiology

Hepatic angiosarcoma represents a very small fraction of all primary liver cancers, accounting for approximately 0.1 to 2 percent of cases. However, despite its rarity, it holds the position of the third most common primary liver cancer. Globally, only around 200 new cases are diagnosed each year, making it an exceptionally uncommon disease that many physicians may never encounter during their careers.^[1][2]

The disease shows a clear pattern in who it affects. Men are diagnosed with hepatic angiosarcoma much more frequently than women, with the ratio ranging from three to four men for every one woman. The typical patient is older, with most diagnoses occurring in people in their 60s or 70s. The peak incidence happens during the sixth or seventh decade of life. Interestingly, this gender pattern reverses in childhood cases, where girls are more commonly affected than boys, though childhood cases remain very rare overall.^[1][3]

When comparing hepatic angiosarcoma to the most common liver cancer, hepatocellular carcinoma (a cancer that starts from liver cells themselves), the difference in frequency is striking. One analysis found that hepatic angiosarcoma occurred in only 0.29 percent of liver cancer cases compared to hepatocellular carcinoma. Despite being rare, understanding this disease matters because it requires different treatment approaches and has a significantly worse outlook than more common liver cancers.^[7]

Causes

The root cause of hepatic angiosarcoma remains unknown in the majority of cases. Approximately 75 percent of tumors develop without any identifiable reason, leaving patients and doctors without a clear explanation for why the cancer appeared. For the remaining 25 percent of cases, several specific causes have been linked to the development of this aggressive cancer.^[1][2]

One of the most well-established causes is exposure to vinyl chloride monomer, a chemical that was formerly used extensively in the production of polyvinyl chloride, a common type of plastic. Workers in factories that manufactured these plastics faced significant exposure to this toxic substance. Back in 1949, scientists recognized that vinyl chloride caused serious damage to the liver and kidneys. The chemical creates a highly reactive substance during manufacturing that harms these organs. What makes vinyl chloride particularly dangerous is that cancer may not develop until about 20 years after exposure, making it difficult to connect the disease to the original exposure. Studies have found that cancers linked to vinyl chloride often have mutations in a gene called TP53.^[1]

Another historical cause involves Thorotrast, which was once used as a contrast material to improve visibility during medical imaging procedures. This radioactive substance was discontinued shortly after its introduction when multiple reports emerged of organ damage and deaths. In the liver, specialized immune cells called Kupffer cells (cells that help filter blood in the liver) take up and store Thorotrast. After these cells die, the substance accumulates in specific areas around the liver’s blood vessels. This leads to scarring of tissue surrounding blood vessels and the liver’s outer capsule. Cancers that develop from Thorotrast exposure often show mutations in a different gene called KRAS-2.^[1]

Chronic arsenic poisoning represents another known cause. When someone ingests arsenic over a long period, the liver initially becomes enlarged. As exposure continues, fat begins to accumulate in liver cells, followed by cell death, scarring, and eventually cirrhosis (severe scarring that prevents the liver from working properly). This progression creates an environment where cancer can develop.^[1]

Additional substances linked to hepatic angiosarcoma include radium, androgenic steroids (hormones that promote male characteristics), diethylstilbestrol, urethane, cyclophosphamide, and oral contraceptives. Some cases have also been associated with conditions like hemochromatosis, a disease where too much iron builds up in the body, and neurofibromatosis, a genetic disorder affecting nerve cell growth.^[1][4]

Risk Factors

While most cases of hepatic angiosarcoma occur without a clear cause, several risk factors increase the likelihood of developing this rare cancer. Having one or more risk factors does not guarantee someone will develop the disease, but it does mean their chances are higher than the general population.^[3]

Occupational exposure to industrial chemicals represents one of the most significant risk factors. Workers in industries that used or manufactured vinyl chloride, arsenic, or Thorotrast faced elevated risks. These exposures were more common in the past before safety regulations improved, which partly explains why most patients are in their 60s and 70s today—they were exposed decades ago when protections were minimal.^[1]

People who underwent radiation therapy in the past for treatment of another cancer face an increased risk of developing angiosarcoma. The radiation that kills cancer cells can also damage healthy cells, including those lining blood vessels. Years or decades later, this damage can lead to cancer developing in these cells.^[3]

Certain rare genetic conditions also increase risk. These include Klippel-Trenaunay syndrome, Maffucci syndrome, and neurofibromatosis. Additionally, people with inherited mutations in genes called BRCA1 and BRCA2, which are more commonly associated with breast cancer risk, may also have a higher chance of developing angiosarcoma.^[3]

The use of androgenic steroids, which some athletes and bodybuilders take to build muscle, has been linked to hepatic angiosarcoma. Similarly, long-term use of oral contraceptives has shown some association with this cancer, though the risk appears to be relatively small. People with chronic lymphedema, a condition causing persistent swelling due to fluid buildup in tissues, may also face increased risk.^[1][3]

Age and biological sex themselves act as risk factors. Being male and being in the sixth or seventh decade of life significantly increases the likelihood of diagnosis. Unlike many other cancers, viral hepatitis does not appear to play a significant role in causing hepatic angiosarcoma, which distinguishes it from the most common liver cancer, hepatocellular carcinoma.^[1][4]

Symptoms

One of the most challenging aspects of hepatic angiosarcoma is that its symptoms are vague and non-specific, meaning they could be caused by many different conditions. This makes early detection extremely difficult. In fact, some people with hepatic angiosarcoma experience no symptoms at all in the early stages, and their cancer is discovered only by accident during imaging tests performed for completely unrelated reasons.^[2][3]

When symptoms do appear, the most common complaint is pain in the upper right part of the abdomen, where the liver is located. This pain may be sharp, dull, or cramping and can sometimes radiate to the back. Patients often describe feeling bloated or experiencing abdominal distension, which occurs when the abdomen becomes swollen and feels tight or full. These two symptoms—abdominal pain and distension—are reported by about 60 percent of people with hepatic angiosarcoma.^[4]

Many patients experience significant weight loss without trying to lose weight. This unintentional weight loss happens because the cancer affects how the body uses nutrients and energy. Fatigue is another common symptom, with patients feeling exhausted even after adequate rest. Some people develop jaundice, a condition where the skin and whites of the eyes turn yellow because the liver cannot properly process a substance called bilirubin.^[2][3]

Additional symptoms can include nausea and vomiting, especially after eating, loss of appetite, general feelings of being unwell (called malaise), and fever. During a physical examination, doctors may detect an enlarged liver or feel a mass in the abdomen. Fluid may accumulate in the abdominal cavity, a condition called ascites, which contributes to bloating and discomfort.^[2]

A particularly concerning symptom occurs when the tumor ruptures. Because angiosarcomas are highly vascular tumors full of blood vessels, rupture can cause severe internal bleeding. Between 15 and 27 percent of patients experience spontaneous tumor rupture, which leads to a medical emergency. People with ruptured tumors may suddenly experience severe abdominal pain, rapid heartbeat, drop in blood pressure, and symptoms of shock. This complication carries an extremely poor prognosis, with patients surviving a median of only 23 days after rupture, even when emergency procedures are performed to stop the bleeding.^[4][6]

Paradoxically, despite these symptoms, liver function often remains relatively preserved until the very late stages of the disease. Blood tests measuring liver function may show only mild abnormalities initially, which can delay diagnosis. This preservation of liver function differs from cirrhosis and some other liver diseases where function deteriorates more obviously.^[4]

Prevention

Because the majority of hepatic angiosarcoma cases occur without any identifiable cause, preventing the disease entirely is not possible for most people. However, for cases linked to known risk factors, particularly environmental and chemical exposures, prevention strategies exist and have proven effective.^[1]

The most important prevention strategy involves avoiding exposure to known cancer-causing chemicals. Workers in industries that use vinyl chloride, arsenic, Thorotrast, or radium should follow all workplace safety protocols strictly. This includes wearing appropriate protective equipment, ensuring adequate ventilation in work areas, and following regulations designed to limit exposure. Since the recognition of vinyl chloride’s dangers, regulations in many countries have significantly reduced worker exposure, which should eventually lead to fewer cases of vinyl chloride-related angiosarcoma.^[1]

For people who have been exposed to these chemicals in the past, awareness of the risk becomes important. Although no specific screening program exists for hepatic angiosarcoma, people with known historical exposure should inform their healthcare providers. This allows doctors to consider this rare cancer if unexplained liver problems develop, potentially leading to earlier diagnosis.^[1]

Since Thorotrast is no longer used in medical imaging and regulations around industrial chemicals have tightened in many countries, fewer people are being exposed to major known risk factors today. This should theoretically reduce future cases related to these exposures, though the long latency period means cases from past exposures will continue to appear for many years.^[1]

For the 75 percent of cases without known causes, no specific prevention measures exist. Maintaining overall liver health through avoiding excessive alcohol consumption, preventing viral hepatitis through vaccination when appropriate, and maintaining a healthy weight may support general liver health, though these measures have not been proven to prevent hepatic angiosarcoma specifically.^[1]

Pathophysiology

Hepatic angiosarcoma begins when something goes wrong in the endothelial cells, which are the cells that form the inner lining of blood vessels in the liver. Normally, these cells create a smooth barrier between the blood flowing through vessels and the surrounding liver tissue. They control what enters and exits the bloodstream and help maintain proper blood flow.^[1]

In hepatic angiosarcoma, changes occur in the DNA of these endothelial cells. These genetic changes cause the cells to lose their normal controls on growth and division. Unlike healthy cells that grow in an orderly way and die when they should, these damaged cells continue multiplying without stopping. They also fail to die when they normally would, leading to an accumulation of abnormal cells.^[2]

As these cancerous endothelial cells multiply, they begin forming new, abnormal blood vessels. This process is not the normal, organized growth of blood vessels that happens during healing or development. Instead, the vessels that form are chaotic, fragile, and leaky. These abnormal vessels eventually cluster together to form tumors. Because the tumors are made up of blood vessel tissue, they contain many blood-filled spaces, making them highly vascular (full of blood vessels).^[1]

The vascular nature of these tumors creates several problems. First, the abnormal vessels are weak and prone to bleeding. This explains why spontaneous rupture with internal bleeding is a relatively common complication. Second, the leaky nature of the vessels means blood cells and fluid can escape into surrounding tissues, contributing to swelling and other symptoms.^[4]

Hepatic angiosarcoma is particularly aggressive because the cancer cells don’t just stay in one place. They have a strong tendency to spread both locally within the liver and to distant parts of the body. The cancer can invade nearby liver tissue and spread through the bloodstream to other organs, most commonly the lungs, bones, and spleen. Because the spleen is close to the liver and also highly vascular, it is a frequent site of spread, and splenic rupture can occur similar to liver tumor rupture.^[4]

Some patients develop disseminated intravascular coagulation, a serious condition where the body’s blood clotting system becomes overactive throughout the bloodstream, using up clotting factors and platelets. This paradoxically leads to both abnormal clotting and dangerous bleeding. This occurs because the many abnormal blood vessels in the tumor trigger excessive clotting activity.^[4]

The liver itself may begin to fail as the cancer grows and replaces normal liver tissue. However, this typically occurs late in the disease course, which is why liver function can appear relatively normal even when the tumor is quite large. When chemicals like Thorotrast or arsenic cause the cancer, they first create other changes in the liver. Thorotrast gets stored in Kupffer cells and causes scarring around blood vessels and the liver capsule. Arsenic causes fat buildup, cell death, scarring, and eventually cirrhosis before cancer develops.^[1]

The genetic mutations found in these tumors vary depending on the cause. Tumors related to vinyl chloride exposure often have mutations in the TP53 gene, which normally helps prevent cancer by controlling cell growth and death. Tumors from Thorotrast exposure frequently show KRAS-2 mutations, which affect cell signaling pathways that control growth. These genetic changes help explain why the cells grow uncontrollably and resist normal death signals.^[1]

Blood tests in patients with hepatic angiosarcoma may show anemia (low red blood cell count), thrombocytopenia (low platelet count), and elevated white blood cell counts. The anemia occurs because of bleeding, either obvious or hidden within the tumor. Low platelet counts result from platelets being consumed in clotting within the abnormal tumor vessels or due to disseminated intravascular coagulation. Interestingly, typical tumor markers used for other liver cancers, such as alpha-fetoprotein, CEA, and CA 19-9, usually remain normal in hepatic angiosarcoma, which can delay diagnosis.^[6]