Angiosarcoma: Survival Rate

Have you worried about a strange looking lump or have been feeling unwell and stumbled upon the word angiosarcoma? Or if your doctor has mentioned it as a potential diagnosis? This article will give you a whistle stop tour of everything you need to know!

What is sarcoma?

Sarcomas are a type of neoplasia. To give you some context, neoplasms are defined as abnormal growths of tissue which are uncontrolled and do not follow the normal pathways of cell lines. Neoplasms can be classified according to their cell line, meaning the starting cell which turned abnormal. For sarcomas, the cell of origin is connective tissue, and therefore are mesodermal in origin. Because they originate from connective tissue, they have wide areas they can affect starting from soft tissue all the way to bone. This gives them a wide region in which they can be found.¹ However, most soft tissue sarcomas (STS) are usually found in the trunk region of the body. In addition, as with most cancers, sarcomas can be further termed benign or malignant. A benign tumor follows a specific set of rules, such as having to stay within the primary location in which they are found. Therefore, if one were to start off in a fatty deposit under the skin, it will not migrate anywhere else nor infiltrate local tissues. Benign tumors also tend to grow at a much slower rate. 

On the other hand, malignant tumors tend to metastasise (i.e. travel to a secondary or tertiary location), infiltrate local tissues, grow at faster rates and alter the normal cell structure or function². Because sarcomas are mesenchymal cell tumors, they will most likely metastasise through the blood, so a common location they travel to is the lungs as they act like sieves where the smallest cells can accumulate. Sarcomas as a whole have been calculated to affect 1% of the human population in the US.  The most common presenting complaint with sarcomas includes hard lumps or pain, which is due to increased pressure on the nerves surrounding it. There seem to be some sarcomas which have a predilection with age, as some are mainly seen in children, this includes osteosarcoma which affect bone, whilst others are seen in older patients like leiomyosarcomas, which are tumors affecting the muscles.  The 2 most common types of sarcomas include liposarcoma, originating from fat tissue, and leiomyosarcomas.

What is angiosarcoma?

Angiosarcomas (AS) are a sub-type of sarcomas. They are of endothelial origin and affect the soft tissues, comprising 1% of all STS. Commonly they affect the skin of the head and neck of older white males. In addition, they can be seen secondary to radiation therapy especially after breast cancer treatment. Sadly, they are known to be malignant and very aggressive so most times prognosis is poor. However, like with most cancers, it is related to how quickly it is diagnosed and how quickly treatment is initialized. Hopefully, by reading further on we can shed some light on the unknown that is AS.

Types of angiosarcoma

Listed below you can find some summarized information about the types of AS. We will cover: Primary AS, Secondary AS, Familial Syndromes and Chemicals.

Primary AS

Due to the nature of AS they can arise from any soft tissue origin. Some of the locations include the skin, the cardiovascular (CV, i.e. the heart and its vessels) system, breast tissue, the liver and the gastrointestinal tract (GIT).³ Cutaneous AS generally presents in older males usually in their 60s. Hepatic AS is really well vascularised due to it being formed in vessels or lymphatic endothelial cells. This usually happens as the hepatocytes (the functional cells of the liver) are taken over and transformed into vasculature for the tumor, which can present as a hard mass. With any bleeding liver mass, AS has to be a differential. Primary breast AS can arise spontaneously but is usually seen secondary to radiation therapy for breast cancer, and there are no noted differences in the 2 in terms of prognosis or development of the disease. Another type of AS is one affecting the GIT. This is much rarer and very few cases have been reported and are more commonly due to metastatic or secondary spread.

Secondary AS

Following radiation therapy 2 types of lesions have been described: Atypical Post-Radiation Vascular Lesions (AVLs) and AS.⁴ AVLs seem to be benign in nature whilst AS is very malignant. Both present with similar lesions (see below under symptoms) but differ in size, with AS being significantly bigger (7.5 cm compared to 0.5 cm in one study) and seem to develop as more of a longer-term consequence (6 years compared to 3.5 years).⁵ In addition, breast AS can also develop due to long term lymphedema following the removal of lymph nodes (LN) related to the breast, which can occur when surgically treating breast carcinoma. Lymphedema can be defined as a swelling due to the lymphatic system not being able to mop up the proteinaceous fluid it would normally uptake. Stewart Treves syndromes is a recognised type of secondary AS. It is a development of AS due to chronic lymphedema. As stated previously, this can be caused by mastectomies and the removal of axillary lymph nodes (LNs), but this syndrome can derive from any long-standing lymphedema no matter the origin.⁶ Lymphedema can be caused by anything impairing the LNs from functioning properly, such as surgically caused lymphedema from the removal of LNs. Other causes include: malignancies of the LNs, obstructive lesions within LNs, infection or trauma to lymph vessels or scar tissue formation within the lymph vessels causing them to not be patent.

Familial syndromes causing AS

There have been studies showing that some genetic diseases could predispose people to AS. Neurofibromatosis type 1 is one of these hereditary conditions that leads to tumors growing around nerves. Another condition is Maffucci syndrome whereby overgrowths of cartilage form, skeletal abnormalities develop and skin lesions with abnormal blood vessels are created. Moreover, another condition is haemochromatosis, thebuild up of iron over the years which can damage organs such as the liver. Lastly, a condition called Klippel–Trenaunay syndrome affects the development of bone, tissue, and blood vessels.⁷ Even though these conditions are associated with AS it does not mean that if you have one of these conditions you will also develop AS, but that there is an increased risk.

Chemicals predisposing AS

Some studies have shown that certain chemicals can predispose to AS. Even though there is not much research into this, vinyl chloride monomer has been linked to hepatic AS. This was usually the case when there were high environmental burdens for workers on chemical plants. This has been reduced in modern days and was typically a problem in the 1970s.⁸ Some other chemicals that have been linked to cutaneous AS include: tetrachloroethylene (PCE), trichloroethylene (TCE) and trans-1-2-dichloroethylene.⁹ PCE is mainly used in the dry-cleaning industry and is still the most common type of chemical used for that industry in the US.¹⁰ TCE instead is mainly used in the making of refrigerants and degreasing solvents. The main way people come into contact with TCE is if it is inhaled or by drinking contaminated water. It used to be used as an anesthetic but has been banned in the US since 1977.¹¹ Trans-1-2-dichloroethylene has been used mainly for cleaning and degreasing, though there is undergoing evaluation for the risk this chemical might pose to the public. But, there is some evidence which links it to the development of AS.¹²

How common is angiosarcoma?

As it has been stated previously, AS is by no means a common condition. It has multiple known types which arequite rare, representing 1-2% of all STS. Out of that small percentage, 60% are made up of cutaneous AS which usually involves the scalp and neck region. After that, it has been found that AS of the extremities is the next most common manifestation. AS can also be linked to familial syndromes with 3% of primary AS involving the passing of genes that can cause predisposition to the cancer.¹³ Breast AS is next with the majority being post radiation therapy, as spontaneous breast AS comprises only 0.05% of all primary breast neoplasm.¹⁴ Hepatic AS follows after that and rounding the end of the list is CV and GIT AS. Therefore, it can be stated that AS is uncommon, but it is important to have it in mind when you develop some symptoms that might concern you.

Symptoms

Due to the wide range of tissues that can be affected by AS, symptoms can be incredibly varied. Seeing as cutaneous AS is the most common, we shall discuss this first. Cutaneous AS should be on your list of differentials if you are suffering from red patches on the skin of your neck and scalp. Some people have also reported little hard lumps on the head and neck. 

If you have AS affecting your CV system, a study has reported the following as the main presenting complaints: weight loss, abdominal pain and difficulty breathing (dyspnoea). In addition, it was found that some of the patients reported an inability to raise their extremities due to the blood supply being blocked.¹⁵ For hepatic AS the symptoms can be non-specific such as tiredness or weight loss. Or slightly more specific with upper abdominal pain and jaundice. As frustrating as it may sound, it can also be asymptomatic, meaning that it is usually encountered by chance such as during imaging. 

On the other hand, the main presenting symptom of breast AS is a painless mass in the breast region. As previously stated AS can be large in size and nodular in appearance, but some people have reported smaller red lesions in the chest area and also diffuse red swellings over the chest. Though the symptoms for GIT AS are rare, they include abdominal pain, bleeding, and anaemia due to the blood loss.¹⁶

Causes and risk factors

Patient groups that are at higher risk of developing AS:

• Older (60-70 years old) white males seem to be predisposed to cutaneous and hepatic AS. However, within children, girls seem to be at greater risk of hepatic AS than boys
• Women who have undergone radiation therapy for breast carcinoma are at higher risk of developing secondary breast AS
• Women who have undergone mastectomies could develop Stewart Treves Syndrome putting them at higher risk

The risk factors can be listed below:

• Previous radiation therapy
• Exposure to carcinogens
• Chronic lymphedema
• Familial genetic conditions

In terms of causes there have been 5 main reported causes: Spontaneous; Exposure to radiation; Chronic lymphedema; Exposure to toxins; and Familial conditions. Sadly, with spontaneous AS it is unlikely that you will be able to pinpoint it to an actual cause. This is because it might have developed on its own or be related to genetic conditions. However, research on this is scarce. An example of chronic lymphedema has been described above as Stewart Treves syndrome. Radiation therapy is a known cause but the actual pathways in which radiation stimulates AS growth is unknown, but it has been postulated to develop from AVLs.¹⁷ In terms of the chemicals in question, they are all carcinogenic which means they stimulate the growth of tumors such as AS but they are not inherently linked to AS.

Diagnosis

One of the main drawbacks of having an incredibly rare condition is that it is usually lower on the list of differentials. In addition, it might also resemble other tumors causing a delayed diagnosis.  The 3 main imaging modalities that can be used by your healthcare provider include ultrasound (US), magnetic resonance imaging (MRI) and computed tomography (CT).¹³ For cardiac AS, echocardiograms can be very useful to identify the location, shape, and size of the tumor,whilst the US of the liver is incredibly helpful for hepatic AS. However, both CT and MRI can be more useful to identify soft tissue masses like AS, especially when trying to differentiate it from other malignancies. Another important test that is used to understand what type of mass a doctor is dealing with is histology. Histology can be used to understand the cellular architecture of tissues which is incredibly helpful when trying to decipher what cell lines are involved and how abnormally they are acting.¹³ There are 3 ways of getting a histology sample: through a biopsy, through complete resection of the mass or a core needle biopsy. These will be chosen at the discretion of your healthcare provider alongside your treatment plan as most of these methods are done alongside surgery. Lastly, another great tool that doctors have is immunohistochemistry. This is a method of detecting specific antigens expressed by cells. For AS the gold standard diagnosis has been through the detection of endothelial marker  CD31.¹³  

Treatments

There are 3 recognised possible treatment options for AS. Local surgery is only possible when there is a discrete mass, and the disease process is largely non-metastatic. Because of the infiltrative nature of the disease, R0 margins are gold standard as that means that even on a cellular level all aspects of the tumor are removed. R1 and R2 carry a worse prognosis. For cutaneous AS especially in the scalp and neck region a type of surgery called Mohs Micrographic Surgery has been shown to be beneficial. It is particularly useful with tumors that have high rates of recurrence and in locations where it is important to spare tissue. The technique includes adding zinc chloride to fix the tissue and allowing the tumor to be resected and observed under a microscope to ensure it is entirely removed.¹⁸ With many surgical protocols other types of therapy can be added on top to improve chances of success. As counter intuitive as it may sound, radiotherapy is actually seen as beneficial when treating AS, and some studies have shown increased survival rates. 

In terms of adjuvant chemotherapy (done with) the surgery, there has been no proven benefit in case studies but it might be beneficial to use it prior to surgery with tumors that are too large to remove on their own. There are 2 main drugs used in chemotherapy when treating AS. A more long-standing group of drugs is the anthracyclines. These cytotoxic drugs (damage cells) have been shown to have a response rate as high as 36% in one study. Another chemotherapeutic group is the taxanes, which are beneficial because of their antiangiogenic properties. This means that they can slow down the rate at which the tumor creates a blood supply or remove it all together. A type of taxane that is used is paclitaxel and weekly injections of it have been shown to help. Targeted therapy has been a recent development that does not seem to be showing clinical benefit. One such drug that seemed helpful was Anti-VEGF (vascular endothelial growth factor) molecules as they target vascular endothelium which AS seems to predilect, and an example drug is bevacizumab. 

Another type of targeted therapy that has not shown much help are Tyrosine Kinase Inhibitors (TKIs) such as Sorafenib. They were hypothesised to be helpful as they target VEGF or PDGFRA (Platelet derived growth factor receptor alpha).¹⁹ However, they also have not shown any clinical benefit. Lastly, a new but untested type of therapy includes immune checkpoint inhibitors (ICI). This is important because cancers have a way to activate immune checkpoints which lead to immunosuppression and worsening prognosis for cancer patients. ICIs could theoretically stop those pathways from being activated. However, some patients developed adverse immune reactions to these drugs. Therefore, there has been a rise in the development of biomarkers which could determine whether a patient would react badly to ICIs or not.¹⁹

Outlook/Prognosis

For any disease there are certain prognostic indicators which can affect the outlook of a disease. When talking about neoplasia it is generally considered that benign tumors carry a better prognosis than malignant ones. Therefore, diagnosing AS before metastasis can be incredibly beneficial. However, due to the rarity and non-specific early signs of this tumor it makes early diagnosis very difficult. Moreover, the ability to completely remove the mass with good margins, if a mass is present, vastly improves the outcome.²⁰ A problem with this is that sometimes the cancerous area is not resectable, either because it encompasses too much tissue or because there is not enough tissue around the tumor to be able to close the surgical site. A study has found that the survival time changes depending on the depth of the tumor in the body. Therefore, it can be said that tumors of the skin carry a better prognostic factor and vice versa for tumors affecting inner organs. 

Furthermore, the staging of the cancer can determine the prognosis. Another prognostic indicator is a smaller tumor. It was found that tumors that were less than 5 cm carried a better outlook. It is understood that late stage AS is less response to treatment especially to the taxane group of chemotherapy drugs.²⁰ However, chemotherapy was found to be most useful when a patient presents with metastasis compared to it having less effect for patients with localized disease. Radiation therapy was found to be a positive prognostic indicator only in specific circumstances. One study found it not to have any beneficial effect in people that begin treatment with metastasis already underway. Also, if someone were to present with the localized cutaneous form and have it surgically resected, radiotherapy was found to not increase chances of survival.

Survival rate

Due to the metastatic nature of the disease the average life expectancy of patients with AS is 6 months to a year and 4 months. One study found that the survival rate (SR) for deep tumors was 5 months whilst for superficial ones it was 60 months.²⁰ Moreover, it was found that patients with tumors smaller than 5cm had a SR of 60 months whilst those with tumors larger than 5cm had 10 months in comparison.²⁰ Furthermore, patients that had surgery seemed to have a SR of over 60 months compared to those that did not have surgery who had a SR of 8 months.²⁰ Still, in terms of treatment the SR of patients receiving radiation therapy for their AS was 47 months compared to 10 months if they did not receive treatment.²⁰ If you have Stewart Treves Syndrome, SR have been hypothesized to be about 10 months.²⁰ Sadly, when looking specifically at hepatic AS, a study found patients to pass away 6 months following diagnosis, and if the tumor ruptures it could be as early as 1 month.²⁰ To not lose all hope, some studies have reported a 5-year survival rate as high as 47%. With improvements in medicines and understanding of the disease this will surely increase with time!

Current research and clinical trials

There are numerous clinical trials at the moment being released to try and improve the treatment for AS. One such trial is involved in looking at therapies that can target something called “endoglin”. And no, as much as it sounds like some sort of alien creature it is something else altogether. Endoglin is a glycoprotein that acts on endothelial cells and is a co-receptor for TGF-alpha but is expressed ad infinitum in AS so that it continuously stimulates it to grow and create a blood supply through angiogenesis (creation of blood vessels). It is hypothesised that by inhibiting endoglin we can potentially prevent the tumor from growing and spreading by cutting off its continuous blood supply. The way the drug is proposed to work in one study is by getting some antibodies to be reactive to endoglin thereby destroying it. In this study it was found to cause apoptosis (cell death) and prevent the spread of AS cells. Therefore, this could be an incredible drug to be used if more evidence supports this theory, as of right now however it is not being used as part of a normal treatment protocol.²¹ Another feature of AS that could benefit from further research is looking at the dysregulation of angiogenic pathways that AS takes over to create its blood supply. This could lead to better understanding of the disease and  to potential new treatments.¹³

Conclusion

Angiosarcoma is a malignant tumor that affects a large variety of tissues in the body. The main types of AS that can be seen include Cutaneous AS, Breast AS (Primary and Secondary), Hepatic AS, Cardiovascular AS and GIT AS. There are numerous causes of AS the most frustrating being spontaneous eruption, but it is also associated with chronic lymphoedema, radiation therapy, certain chemicals, and hereditary conditions. The symptoms are related to the type but most patients present asymptomatically. This is a big setback in diagnosing the disease and is a negative indicator for prognosis because it is best to catch it in the earlier stages. This is because it will metastasise, most commonly to the lungs and the brain, at which point it might be too late. In order to diagnose it, imaging is essential with a plethora of choices such as ultrasound, MRIs, and CT. In addition, it is important to biopsy the tumor to then send it off for histology to assess the cellular architecture of the mass, as this will allow staging of the disease and aid in the choice of therapeutics. There are multiple treatments for AS with by far the best one being surgical resection with R0 margins, so no cancer cells are left behind. The best technique for skin lesions is the Mohs Micrographic Surgery technique. Moreover, radiation therapy yields great results and chemotherapeutic drugs seem to be effective to a point, especially the taxane group. Sadly, the prognosis for this condition is quite poor and tends to be invariably fatal. However, a study found that 47% of patients could make it to a 5-year survival rate. In addition, there are current clinical trials and potential research that could revolutionize the diagnosis and treatment of AS and hopefully lead to an increased life expectancy for people suffering from this condition.