Also known as:

  • LMS
  • Uterine Leiomyosarcoma (ULMS)
  • Tumours in individual sites might be given a more detailed name that includes the organ it affects e.g. liver leiomyosarcoma, or cutaneous leiomyosarcoma (skin).
  • Previously GIST (gastrointestinal stromal tumour) was considered to be a type of leiomyosarcoma, but it is now known to have a very different biology and is now considered as a separate disease.

Contents

How rare is leiomyosarcoma?

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.

In the UK leiomyosarcoma is the third most common soft tissue sarcoma after GIST and undifferentiated sarcoma with around 500 cases per year or 0.74 cases per 100,000.

As uterine leiomyosarcoma (a womb cancer) makes up around half of cases it appears to be more common in women. For non-uterine leiomyosarcoma it tends to occur more often in the retroperitoneum (the area at the back of the abdomen) and blood vessels in women and in the skin and other soft tissues in men.

Leiomyosarcoma is usually a disease of older adults, typically in their 60s and 70s, although uterine leiomyosarcoma tends to occur in perimenopausal women between 40 and 50.

There are very few factors that increase the risk of developing leiomyosarcoma. Certain genetic disorders increase the chance of developing many cancers including leiomyosarcoma (Li-Fraumeini syndrome and inherited retinoblastoma)as does exposure to radiation.

Finally, there is a very rare form of leiomyosarcoma that is associated with infection with Epstein Barr virus in people who have weakened immune systems or have to take immunosuppressive drugs after a transplant.

What is leiomyosarcoma?

Leiomyosarcoma is a type of sarcoma, a cancer that affects soft tissues. In this case the soft tissue involved is the smooth muscle, or cells that will eventually develop to become smooth muscle.

What is smooth muscle?

Muscle is a tissue in your body which can contract, or pull, to move, pump or squeeze parts of your body. Most people are aware of their skeletal muscles that are used to consciously move our bodies. Many of them are near the surface and easily felt or seen – the biceps in our upper arm, or the hamstring at the back of the thigh for example.

Our heart is made up mostly of a second type of muscle called cardiac muscle which contracts thousands of times a day to pump blood around the body. This muscle never gets tired and we have no conscious control over it.

The third type of muscle is less obvious, this is smooth muscle. It is found in many parts of the body – in the digestive system, where it contracts to mix food in the stomach and squeeze it through the intestines. It lines the bladder and helps to control the way it fills and empties. Smooth muscle lines the airways – anyone with asthma will be familiar with what happens when this muscle contracts when it shouldn’t. The uterus or womb has smooth muscle that supports it and is responsible for the contractions of childbirth. Smooth muscle lining the blood vessels helps maintain your blood pressure. There is even smooth muscle in the skin where tiny muscles contract to make your hair stand on end.

Normally strict controls make sure that cells only divide at the right time and develop into the right type of cell for where they are in the body. When this goes wrong, cells divide uncontrollably, they can behave like other types of cells or even develop features that are never seen in any normal cell . When this happens to smooth muscle cells or cells that are programmed to become smooth cells the cancer that develops is called a leiomyosarcoma.

Leio=smooth myo= muscle sarcoma= a cancer of connective tissue

Any smooth muscle in the body can develop a leiomyosarcoma, but the most common places are the abdomen, uterus, retroperitoneum and major blood vessels. Only 10-15% of leiomyosarcomas form in the limbs, whilst sites like the eye are extremely rare.

Diagnosing leiomyosarcoma:

Leiomyosarcoma may be found as a lump that has developed on the body or due to symptoms caused by it developing in a way that it affects the function of a nearby organ. There may be abdominal pain, digestive discomfort, swelling or bloating. If the tumour is in the uterus there may be unexplained vaginal bleeding.

Sometimes the tumour is only discovered after surgery, such as hysterectomy (removal of the womb). A range of scans, X-ray, PET, CT and MRI which all give slightly different images of the inside of the body can be used to locate a tumour precisely and from the appearance in these images give an idea of what type of tumour is present.

Tumours that are still in the body will usually have a small piece of tissue removed – a procedure called a biopsy. This will be studied by histologists (scientists who study cells and tissues using microscopes)to confirm whether the tumour is benign or a cancer, and if so, which type of cancer it is.

Leiomyosarcoma can be confirmed either directly from the way the cells appear and their arrangement in the tumour or by using special stains that detect molecules that are commonly found in smooth muscle. Ones that might be mentioned in histology reports are: alpha smooth muscle actin, desmin and H-caldesmon, although they are not only found in smooth muscle. It is the combination of symptoms, scans and histology that is used to give the most likely diagnosis.

Genetics:

Most cancers have genetic mutations, changes to the DNA instructions within cells, that allow them to divide uncontrollably and eventually spread to other places (metastasis). Some cancers have characteristic mutations that can be used to help diagnose the cancer and also to help scientists develop new drugs that stop the consequences of that mutation.

Leiomyosarcoma does not have a typical mutation. Instead it can have many changes and the more there are, the more aggressive the cancer is likely to be.

Scientists have studied the mutated genes in leiomyosarcoma and have found that although there is a complex mix of changes, some are more common than others. They are called TP53, Rb1 and PTEN (unfortunately genes don’t have very helpful names). They are all the instructions for making parts of the machinery that controls cell division, preventing it from happening uncontrollably. This type of gene and the proteins they are the instructions for are called tumour suppressors, because mutations that stop them working can lead to cancer developing.

In some people inherited mutations in the TP53 gene are associated with a condition called Li-Fraumeni syndrome which makes them more likely to develop cancers, including leiomyosarcoma. At the moment there are no drugs that can stop the effects of these mutations directly. Also the wide range of genetic mutations seen in leiomyosarcoma means that different treatments may affect different leiomyosarcoma tumours differently. This means it can be hard to understand the results of clinical trials or recruit the most suitable patients to a trial. However DNA sequencing of tumours is becoming more common and scientists are developing drugs that affect cancers that have particular mutations. Because they are designed to target the mutation and not the specific cancer these may prove useful in treating leiomyosarcomas that share these mutations.

Uterine leiomyosarcoma (ULMS):

As scientists have learned more about leiomyosarcoma they have found that uterine leiomyosarcoma has enough differences from leiomyosarcoma that forms in other places to treat it as a separate sub-type.

Although uterine leiomyosarcoma is the commonest form of leiomyosarcoma, accounting for just over half of all cases it is still a very rare form of womb cancer. It accounts for at most, 5% of all womb/uterine cancers. The only extra risk for this cancer is possibly using the drug tamoxifen (taken after breast cancer) for a long time causes a few extra cases, although there is not yet enough evidence to be certain.

It is often difficult to treat and usually quite aggressive, 55-70% of these tumours become metastatic, especially if they have regrown after surgery. The most common sites for secondary tumours are the lungs, peritoneum and bones.

Analysing the DNA of these tumours found mostly the same genetic mutations as in leiomyosarcomas that form elsewhere. Some genetic mutations were only found in leiomyosarcoma that starts in the uterus. Interestingly some of these mutations were in the BRCA1/2 genes that are well known for being associated with breast cancer which means that the 10% of patients whose tumour has these mutations may be able to benefit from drugs developed for treating BRCA1/2 breast cancer.

Uterine leiomyosarcoma and fibroids:

ULMS often look and behave like a benign (non-cancerous) leiomyoma. Leiomyomas are more commonly known as fibroids. Fibroids are the commonest growths that develop in younger women’s reproductive organs. They vary in size, and larger, or awkwardly placed ones can cause bleeding or discomfort. Ones that cause problems may need to be removed by surgery. Very occasionally what was thought to be a fibroid turns out to be a leiomyosarcoma when it is examined after surgery, but there is no evidence that fibroids can become malignant.

Non-uterine leiomyosarcoma:

Any smooth muscle tumour found outside of the uterus is usually assumed to be malignant (cancerous) as cases of benign smooth muscle tumours of this type are extraordinarily rare.

They are aggressive tumours, with a high chance of becoming metastatic and invading other tissues and organs, especially the lungs and liver. The smooth muscle cells they form from can be found anywhere in the body – as well as forming part of organs, smooth muscle is found in veins and arteries, so tumours can potentially form anywhere. Some sites are more common than others, but there are reports of leiomyosarcomas in every part of the body.

The place they form in can affect how the disease progresses. Tumours that form in the abdomen are more likely to be metastatic than ones found in the limbs, although this may be affected by the length of time before abdominal tumours are noticed.

What are the current treatment options for leiomyosarcoma?

Surgery to remove the tumour is usually the first option. For uterine leiomyosarcoma, this may have been done before the sarcoma was discovered. Surgery will usually aim to get what is known as an R0 resection, sometimes called a negative margin, where an area of healthy tissue from around the tumour is also removed to be certain that there are no cancer cells left, even when checked with a microscope. When the tumour is in a limb surgeons will attempt to remove the tumour, protecting nerves and blood vessels and reconstructing the area.

Radiotherapy (RT)

For uterine leiomyosarcoma studies have found that there is no real benefit of giving patients radiation treatment except when the tumours have spread and it can be used to help control symptoms from these extra tumours.

For all other leiomyosarcomas RT is commonly used before or after surgery. The timing when this happens has to balance the different side-effects that can occur. Before surgery, RT can affect the ability of the wound to heal. If used afterwards patients are more likely to have fibrosis (thickening and scarring) and joint stiffness.

Chemotherapy/targeted therapy:

When chemotherapy is given around the time of surgery, it is called adjuvant therapy. There have been several clinical trials using common chemotherapy drugs such as doxorubicin and ifosfamide, either before or after surgery, but the results have been variable and don’t show a clear enough effectiveness to justify them being used for most patients.

If the disease has become metastatic, chemotherapy is used to help slow the growth and spread of the tumours. Uterine leiomyosarcoma and larger tumours tend to respond better in this case. Common first-line (first to be used) drugs are doxorubicin (adriamycin) and gemcitabine combined with docetaxel. These toxic drugs damage the DNA of dividing cells so that the cells can no longer survive.

Some second line drugs that might be used are:

Trabectedin (Yondelis), a drug first found in a sea squirt, sticks to DNA and damages it. This drug can be used with other chemotherapy drugs either as a first treatment or a second treatment if the first stops working.

Olaratumab is a type of drug called a monoclonal antibody. They stick to a particular molecule in the body, in this case a messenger called PDGFRa, that helps switch on cell division. Olaratumab sticks to it, stopping it from acting on the cancer cells and reducing their rate of growth.

Eribulin is another drug that was found in a sea sponge. This one prevents cells from completing the final step of cell division. It has been found to slow the progress of the disease in some patients.

Pazopanib is from a family of targeted drugs called tyrosine kinase inhibitors that can switch off the messages that tell cancer cells to divide. Trials have found that it can stop the disease progressing as quickly.

PARP inhibitors (Olaparib). PARP is the short name for part of the body’s DNA repair mechanism. Drugs like Olaparib stick to PARP and trap it in the DNA. Normal cells can fix this damage, but cancer cells often have a broken DNA repair system, and the cancer cells can’t fix themselves and die.

Future Drugs:

Scientists have found that leiomyosarcomas contain a lot of cells from the immune system and are working on ways to help the immune system attack and destroy the cancer cells. They are also looking at other ways of affecting the cancer cells ability to repair DNA damage and for some hormone sensitive cancers, preventing them responding to hormones such as oestrogen.

What are the current clinical trials for leiomyosarcoma?

Information current as of: 25-04-23

Globally, there are nearly 200 trials, of which three are actively recruiting specifically for leiomyosarcoma in the UK.

One is looking at the drug unesbulin, which affects the ability of cells to divide, another is looking at the effectiveness of the tyrosine kinase inhibitor sunitinib and the immune activating drug nivolumab alongside standard chemotherapy treatments, the third is studying a drug called tabelecleucel for Epstein Barr associated tumours and the last is looking at the effectiveness of chemotherapy before surgery for leiomyosarcoma in the retroperitoneum.

Where can I find leiomyosarcoma support groups?

Name

Website

Notes

Sarcoma UK

The main UK sarcoma support site

Sarcoma support groups

A list of local and online groups for general sarcoma or more specific conditions

Awareness and symbols

All sarcomas have July as their awareness month.

The ribbon for sarcomas is yellow