Also known as:
Hemangiosarcoma – when it forms in blood vessels
Lymphangiosarcoma – when it forms in lymph vessels
How rare is angiosarcoma?
In the UK and Europe the usual definition of a rare cancer is one that occurs in less than 6 people out of every 100,00 each year. Because there are around 200 rare cancers, this means that they make up about 24% (nearly a quarter) of all cancers.
According to Sarcoma UK, there are typically 164 cases of angiosarcoma each year diagnosed in England. This makes it a very rare cancer with an incidence of 0.29 cases per 100,000 people. It can appear at any age, although it is more common in older adults. Most patients are over 60 and it is slightly more common in males.
What is angiosarcoma?
Angiosarcoma is a type of cancer, called a sarcoma. Sarcomas are a family of rare cancers that start in the soft tissues of the body – muscle, fat, nerves and blood vessels as well as bones.
Angiosarcomas form from cells that are part of all blood and lymphatic vessels in the body.
The pictures below show the simple structure of three types of blood vessels. You can see that the arteries that carry blood under high pressure from the heart have several layers. These layers include muscle and tough connective tissue to withstand the pressure of the blood as it leaves the heart (there is more detail in the second picture). Veins that return blood to the heart have thinner walls and have wider spaces inside, as they are not under high pressure. Capillaries have the thinnest walls as substances like oxygen and glucose need to get out into the surrounding tissues.
Lymph vessels look quite like capillaries and carry white blood cells and fluid released by cells back to the bloodstream.
The inner layer of all of these vessels is made of flat endothelial cells. The picture below shows a section of an artery with its different layers and the endothelial cells on the inner surface. This means that endothelial cells are in direct contact with the bloodstream as well as the lymphatic system.
It is the endothelial cells that divide uncontrollably in angiosarcoma. As there are blood and lymph vessels spread through the whole body, angiosarcoma can develop anywhere, although certain sites are much more common than others.
The most common site is the skin where about 60% of cases develop, often on the head and neck, especially in areas that are exposed to the sun.
In skin angiosarcoma first appears as one or more bluish or purple bruise-like marks that grow and bleed easily when knocked. It can sometimes be mistaken for a form of skin cancer called melanoma before further tests can confirm what it actually is.
Angiosarcoma can also develop in the liver, where the developing tumour can cause pain and jaundice as it affects the ability of the liver to function. Other places where angiosarcoma has been found include the bones, kidneys, breast and very rarely, the heart.
Scientists have not identified any clear cause of angiosarcoma. Links have been found to certain chemicals such as vinyl chloride (from making plastics) , arsenic from the workplace or the environment and a radioactive substance called thorotrast that used to be used to improve X-ray images. These are especially associated with angiosarcomas in the liver.
Angiosarcoma is also linked to some extremely rare inherited conditions that increase the risk of particular cancers, such as Maffucci syndrome and Ollier disease.
There is a possibility that exposure to UV light might be a risk factor for angiosarcoma in the skin as many of them form in sun exposed areas on older white skinned men.
Another risk factor is chronic lymphoedema where damage to the lymphatic system from disease or cancer treatment, especially when lymph nodes have been removed, leads to swelling in the affected part of the body. This condition is called Stewart-Treves syndrome after the doctors who first described it. For more information about the lymphatic system watch this clear video from CRUK. Lymphoedema can also be associated with the final risk factor for people who have had radiotherapy, especially for breast cancer or Hodgkin lymphoma where it combines with the gene damaging effects of the radiation leading to the appearance of angiosarcomas up to 15 years after the original treatment finished.
Angiosarcoma is often an aggressive cancer with a tendency to metastasise (spread) easily, especially to the lungs and liver. They also tend to recur after surgery. The development of new treatments has been difficult because of the rarity of angiosarcoma, but new approaches to cancer, that target features of the cancer cells biology that are shared with many cancers and treatments that help the immune system to find and destroy cancer cells may improve outcomes for people with angiosarcoma.
The bruise-like appearance of angiosarcoma on the skin, especially, the head and neck or previous radiotherapy for breast cancer and developing lymphedema is a clue to the diagnosis of angiosarcoma. If the tumour has formed inside the body, there may be pain where the developing tumour presses on nerves or symptoms caused by the tumour affecting the function of that organ. Confirming a diagnosis will need a combination of scientific methods as angiosarcoma can look like other types of cancer such as melanoma or Kaposi sarcoma.
Imaging scans (CT, MRI, ultrasound etc) can confirm the shape and size of the tumour and if it has spread (become metastatic). Secondary tumours tend to be found in the liver and the lungs, probably because they are easily reached by tumour cells entering the bloodstream.
Biopsy – looking at the tumour cells.
Further clues can be found by studying the tumour cells under a microscope which needs a biopsy – a small piece of tissue taken from the tumour. This might be taken on its own or during surgery to remove the tumour.
The histologist (a person who studies cells) looks for features that are typical of endothelial cells or previously identified angiosarcomas. This can be difficult as the appearance and behaviour of cells in angiosarcomas can be very unusual as the cells no longer look or grow like endothelial cells (they have become undifferentiated).
In order to help identify the type of cells, histologists will use special stains that stick to substances that are commonly found in endothelial cells. These have rather unhelpful names – Factor-VIIIRA, CD31, CD34 and vascular endothelial growth factor (VEGF), but may appear on a report confirming that a tumour is probably angiosarcoma. Other stains that can detect the presence of a virus associated with Kaposi sarcoma, or features associated with melanoma to help rule these out as a possible alternative diagnosis.
The final test that can help identify the cancer is genetic analysis which might direct doctors to suitable treatments depending on the results.
In the nucleus of our cells is the iconic molecule of inheritance, DNA. It looks like a twisted ladder with four types of rungs, where the order of the rungs acts as a simple alphabet, spelling out the instructions for everything that our cells make and do. A gene is a short section of the DNA that contains the instructions for making one protein – proteins make up much of our bodies and have many other functions including controlling what cells do.
We can find the order of the letters in any gene by sequencing the DNA. Changes to the sequence are called mutations. Some mutations have little effect on us, but others can lead to cancer by changing the amount or activity of the proteins that are made.
Scientists have analysed the DNA sequence of many tumours from people with angiosarcoma.. Some cancers have a very characteristic mutation that can be used to both confirm the diagnosis and as a potential target for developing drugs to treat the disease. Others are more complicated.
Angiosarcoma does not have a particular mutation that can be used to identify it with certainty. The most common mutations in angiosarcoma are in genes called MYC, TP53 and KDR and FLT4 (gene and protein names are not always helpful for non-experts). About 40% of angiosarcomas have extra copies of MYC. MYC is the gene for a protein that controls the production of many other proteins involved in cell division. In some cancers there are extra copies of MYC, which means the rate of cell division goes up . TP53 is called the guardian of the genome as it produces a protein that is involved in repairing damage to DNA, many cancers have mutations in this gene that stop it working properly.
Chemicals produced by the body control the growth, properties and behaviour of blood vessels. KDR is the gene for a protein that is found on the surface of cells in blood vessels, it is something called a receptor. These chemical messengers stick to the receptor which passes the message into the cell and it will respond to the message. In angiosarcoma mutations can produce more KDR than is needed or make it behave as if it has stuck to a chemical message, even if there isn’t one.
FLT4 is similar to KDR, but for slightly different chemical messages, although it is still part of the regulation of blood vessels.
The NHS will also do tests for other genes called NTRK1/2/3. These are also receptors which can be mutated to a form that tells cells to divide uncontrollably. Although very few angiosarcomas will have this mutation, drugs that stop NTRK acting (larotrectinib) can help slow the disease if a patient has tested positive for it.
What are the current treatment options for angiosarcoma?
As with most sarcomas, surgery is the main treatment. A surgeon will attempt to remove the tumour along with some healthy tissue around it. This is called “taking a margin”. Tissue from the edge of the area will be checked under a microscope to see if any tumour cells remain. If there are none visible it is called an R0 surgery ,or having a negative margin, tumour cells only visible under a microscope is R1, whilst visible tumour remaining is R2. IIf any of the tumour is left it is called having a positive margin. The size and location of the tumour will affect how much can be removed as surgeons may need to avoid damaging important parts of the body. The delicate and important nerves and blood vessels in the head and neck can make it difficult to completely remove the tumour and surgery for an angiosarcoma in the heart will always be difficult.
Radiotherapy uses beams of high energy radiation to kill tumour cells. Whilst sparing healthy tissue. In angiosarcoma it may be used before surgery to reduce the size of a tumour, after surgery to ensure that all of the cancer cells have gone or to help treat complex tumours that can’t be removed by surgery.
Scientists have found that routinely giving patients chemotherapy before or after surgery does not have much benefit. Many patients are also older and less able to tolerate the toxic drugs involved. Chemotherapy is only usually used for angiosarcoma that has become metastatic.
The chemotherapy drugs that are used are mostly doxorubicin and ifosfamide. These chemicals damage the DNA of dividing cells, eventually killing them. Because they affect all dividing cells they cause many of the familiar side-effects of chemotherapy.
Another drug, called olaratumab (Lartruvo) can be given with doxorubicin. This is an altered version of an antibody – a molecule usually made by your immune system to recognise and target pathogens. Olaratumab recognises and sticks to a receptor molecule on the surface of cells that normally receives messages telling the cells to divide. By blocking the receptor, the message can’t get through.
Taxanes are another family of drugs that are sometimes used. The commonest is paclitaxel, which interferes with the machinery that moves DNA to the correct place when cells divide.
Targeted and Immunotherapies:
Because angiosarcoma starts in cells that are part of the network of blood and lymph vessels they have certain features that can be used to develop drugs to stop them dividing uncontrollably. Studies have been completed looking at blocking messages that are sent through a chemical called VEGF that stimulates the creation of new blood vessels. Drugs called pazopanib and sorafenib have shown some effect in trials but are not yet routinely used.
Immunotherapy is designed to stop the tumour hiding from the immune system. Cells of our immune system have a mechanism that stops them attacking and destroying normal healthy cells. They have a receptor on their surface called PD-1. Many cells make a molecule that sticks to PD-1, stopping the immune cells attacking. This is important for normal cells. Many cancers also produce a lot of this molecule which helps hide them from the immune system. Drugs called checkpoint inhibitors (pembrolizumab and nivolumab are two) can stop this happening, allowing the immune system to destroy the cancer cells.
What current clinical trials are there?
Information current as of: 7th June 2023.
The only current trial for angiosarcoma in the UK is the IMMUNOSARC trial which is looking at the combination of sunitinib, a drug that blocks the transfer of “grow” messages in the cancer cells and nivolumab.
Awareness, events and symbols
All sarcomas have July as their awareness month.
The ribbon for sarcomas is yellow.