Soft Tissue Sarcoma
by I. Boukovinas, M.D., Medical Oncologist

Introduction

Soft tissue sarcomas (STS) are tumors that originating from cells in the soft tissues that surround, connect or support the body’s structure and organs. This includes fat, muscle, nerves, fibrous tissues, joints, tendons, and blood vessels.

They also can begin in the body’s organs such as the uterus, stomach, skin, and small bowel and in general, soft tissue sarcomas can develop in any part of the body.

Some soft-tissue tumors are benign (not cancer), and others are malignant (cancer). When the term sarcoma is part of the name of a disease, it means the tumor is malignant. For example lipomas are benign tumors of fat tissue and liposarcomas are malignant tumors of fat tissue. They are a heterogeneous group of rare tumors and each type of sarcoma is named after the type of cell it started from, rather than the part of the body where it started to grow.

STS have more than 50 distinct histological subtypes, with leiomyosarcoma, liposarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumors being among the most common subtype.

 

Etiology-epidemiology

Nobody knows the causes of soft tissue sarcomas.

Some conditions can be a risk factor for developing sarcomas. Patients might develop sarcomas from radiation given to treat other cancers, like breast cancer or lymphoma.

An inherited faulty gene that can be passed on to other family members does not cause most sarcomas. Members of a sarcoma patient's family are not likely to have an increased risk of developing a soft tissue sarcoma.

Certain inherited conditions increase a person’s risk of developing soft tissue sarcomas, like:

  • Neurofibromatosis
  • Gardner syndrome
  • Li-Fraumeni syndrome
  • Retinoblastoma
  • Werner syndrome
  • Gorlin syndrome
  • Tuberous sclerosis

Furthermore, exposure to some chemicals, like vinyl chloride (a chemical used in making plastics), arsenic, dioxin and to herbicides that contain phenoxyacetic acid at high doses (such as might occur to people who work on farms) can cause sarcoma. There is no evidence that herbicides or insecticides, at levels encountered by the general public, cause sarcomas.

Also, there is no evidence that an injury is a risk factor for a sarcoma. Usually, because of an injury, a systematic imaging is done and an already existing sarcoma is discovered.

Soft tissue sarcomas occur rarely and account for approximately 1% of malignancies in adults and 2% of cancer mortality. Slightly more than half of these are in males. Some types of sarcoma occur in children, teenagers and young adults, but generally they are more likely to develop in people over the age of 30.

Nearly half of the patients diagnosed with soft tissue sarcomas develop advanced/metastatic disease and eventually die from the disease.

 

Clinical Symptoms

The symptoms will depend on the part of the body that is affected. Sarcomas often are "silenced" for a long period of time. As the tumor grows, it may cause:

  • a noticeable lump anywhere in the body, especially if it is increasing in size and is bigger than 5cm and is deep in the body
  • pain, if it presses on nerves or muscles
  • a blockage or bleeding of the stomach or intestines

Since symptoms of soft tissue sarcomas often become apparent in advanced disease, only about half of the cases are found in the early stages, before they have spread.

 

Diagnosis-Staging

There are neither tumor markers for sarcomas nor specific blood tests.  The diagnosis of sarcoma is usually made with a biopsy, a test where a sample of tissue is removed from a tumor to see if it is a type of cancer. The decisions involved in the biopsy approach can be complex and are best made by a sarcoma specialist team.

Several types of biopsies are used to diagnose sarcomas. Tissue samples can be obtained through fine needle aspiration or needle core biopsies or through open surgical methods. Since many soft tissue sarcomas are easy for physicians to locate and feel, needle biopsy is often all that is necessary and core needle is preferred in order to remove enough tissue for a more precise diagnosis. Needle biopsies are frequently performed by radiologists under computed tomography guidance.

Sometimes biopsy through an incision in the skin (called incisional biopsy) is necessary because it allows for the removal of more tissue for evaluation. If the tumor is near the skin surface, this is a simple operation that can be done with local or regional anesthesia. But if the tumor is deep inside the body, general anesthesia is used. Excisional biopsy (a biopsy that removes the entire tumor) should be avoided in most cases of suspected sarcomas. An improper biopsy can lead to tumor spread and problems removing the tumor later on.

After the biopsy, a pathologist looks at the tumor tissue under a microscope to make a diagnosis and to determine the tumor's grade (which indicates how aggressive the tumor is). The classification of the grading is:

  • Grade 1 (or low-grade, or well differentiated): The cancer cells look similar to normal cells, usually grow slowly, and are less likely to spread.
  • Grade 2 (or moderate- or intermediate-grade): The cancer cells look more abnormal, and are slightly faster-growing.
  • Grade 3 (or high-grade or poorly differentiated): The cancer cells look very different from normal cells, and may grow even more quickly.

The determination of which sarcoma a patient is diagnosed with should be done by a skilled pathologist with extensive background in sarcoma pathology. Results of the biopsy can take up to ten to fifteen days to get all of them. This can be a worrying time, but it is very important that an accurate diagnosis is made so that the most appropriate treatment can be given.

 

The performed imaging tests include:

  • Computed tomography (CT) of thorax and abdomen. CT scans might be done to precisely guide a biopsy needle into a tumor that is inside the body or looking for the extension of the disease to other organs.
  • Magnetic resonance imaging (MRI) especially for sarcomas of legs, arms and head and neck for their precise location and their relation to surroundings organs.
  • Positron emission tomography (PET) scan. PET is not often used for sarcoma, but it can be helpful in certain cases of doubt and in some centers for quick evaluation of response to treatment.

 

Based on these tests the tumor is usually classified into one of the following 4 categories, which may be further sub-divided:

  1. Stage 1 sarcomano spread to lymph nodes or other parts of the body. Grade may be low or unknown, and it can be either superficial or deep within the body. There are two sub-divisions of Stage 1 sarcomas:
  • Stage 1A: The tumor is small (5cm or less).
  • Stage 1B: The tumor is larger than 5cm.
  1. Stage 2 sarcomano spread to lymph nodes or other parts of the body. It can either be superficial, or deep within the body. There are two sub-divisions of Stage 1 sarcomas:
  • Stage 2A: The tumor is small (5cm or less), and either moderate- or high-grade.
  • Stage 2B: The tumor is larger than 5cm, and moderate-grade. 
  1. Stage 3 sarcomaIt can either be superficial or deep within the body, and either:
  • The tumor is bigger than 5cm and high-grade, and has not begun to spread, or
  • The tumor is of any size, of any grade, but it has spread to at least one lymph node, but not to other parts of the body.
  1. Stage 4 sarcoma:
  • The tumor can be of any size, and of any grade. It can be superficial or deep. It may or may not have spread to lymph nodes, but it has spread to another part of the body (such as the lungs, liver, bones or soft tissues). Stage 4 soft tissue sarcoma is also known as secondary or metastatic.

 

Pathology

Below are some common types of Bone and Soft Tissue Sarcomas

  • Alveolar soft-part sarcoma is a rare cancer that mostly affects young adults. These tumors most commonly occur in legs.
  • Angiosarcomas are malignant tumors that can develop either from blood vessels (hemangiosarcomas) or from lymph vessels (lymphangiosarcomas). Angiosarcomas are sometimes seen in the breast after radiation therapy for breast cancer, and in limbs that are chronically swollen because lymph circulation is blocked (lymphedema).
  • Chondrosarcomas are malignant tumors that begin in cartilage. They typically occur in patients between age 50 and 80, and commonly occur in the pelvis or femur.
  • Dermatofibrosarcoma protuberans is a malignant tumor that grows beneath the skin, usually in the arms and legs or trunk. It grows into nearby tissues but rarely spreads to distant sites.
  • Desmoplastic small round cell tumor is a rare sarcoma of adolescents and young adults, found most often in the abdomen. Its name means that it is formed by small, round cancer cells surrounded by scar-like tissue.
  • Ewing sarcoma is a small round blue cell tumor that typically occurs in the bones of patients less than 20 years old. There are variants that occur in the soft tissues (primitive neuroectodermal tumor, or PNET) of elderly.
  • Fibromatosis (or desmoid tumors) is the name for a group of benign slow-growing tumors in the fibrous tissue. They do not spread to distant sites, but they do cause problems by growing into nearby tissues. Certain hormones, particularly estrogen, make some desmoid tumors grow.
  • Fibrosarcoma is a more cancerous tumor of the fibrous tissue and most commonly grows in the legs, arms, or trunk. It is most common in people between the ages of 20 and 60, but can occur at any age, even in infancy.
  • A gastrointestinal stromal tumor is a type of sarcoma that develops in cells in the wall of the gastrointestinal tract, which can include the esophagus, stomach, rectum, or small intestine.
  • Hemangioendothelioma is a slow-growing cancer that forms in blood vessels. It may start in organs such as the liver and the lungs and sometimes can spread to distant parts of the body.
  • Hemangiopericytoma is found around blood vessels. It can be either malignant or benign. It most often occurs in the legs, pelvis, and the back of the abdominal cavity.
  • Kaposi sarcoma develops from cells called endothelial cells. Most cases occur in the skin but it can also develop in internal organs of the body. Colored nodules develop on the skin, in the mouth and lymph nodes, and in organs such as the lung, liver and spleen. It occurs most often in people with suppressed immune systems, including people with HIV and those who have taken immunosuppressive drugs because of an organ transplant.
  • Leiomyosarcomas are malignant tumors of smooth muscle found in the uterus, gastrointestinal tract, or the blood vessels. These tumors are less often found in the deep soft tissues of the legs or arms. They tend to occur in adults, particularly the elderly.
  • Liposarcomas develop from a fat cell precursor and can occur in any part of the body; they are usually found in the thigh or behind the knee, and inside the back of the abdomen. They occur mostly in adults between 50 and 65 years old.
  • Malignant fibrous histiocytoma, also known as undifferentiated pleomorphic sarcoma, occurs most commonly in the legs and is the most common soft tissue sarcoma. Although it mostly tends to grow locally, it can spread to distant sites.
  • Malignant peripheral nerve sheath tumors, neurofibrosarcomas, malignant schwannomas, and neurogenic sarcomas are malignant tumors of cells that surround a nerve.
  • Osteosarcomas are the most common sarcoma of bone. They occur most commonly around the knee of teenage patients. Treatment for most osteosarcomas involves chemotherapy and resection of the tumor. This often requires a skeletal reconstruction.
  • Rhabdomyosarcomas are malignant tumors of skeletal muscle. These tumors commonly grow in the arms or legs, but they can also begin in the head and neck area and in reproductive and urinary organs like the vagina or bladder. They occur in children. There are two main types of rhabdomyosarcoma – embryonal and alveolar. Embryonal rhabdomyosarcomas tend to occur more commonly in children and young people. Alveolar rhabdomyosarcomas tend to occur more often in younger adults. There is a third type called pleomorphic rhabdomyosarcoma. This is rare and tends to occur in adults.
  • Synovial sarcoma is a malignant tumor of the tissue around joints (the synovium). The most common locations are the knee and ankle. Other sites are the shoulder and hip. It most often occurs in children and young adults but can also be found in older adults.

 

Treatment Strategies

Basic principles

As sarcomas are rare cancers, the patent should always be referred for treatment at a specialist sarcoma unit where a team of specialist doctors and others work together. This is known as a multidisciplinary team (MDT) and will include:

  • A surgeon who specializes in sarcomas
  • A medical oncologist who specializes in sarcoma’s treatments such as chemotherapy, and biological therapy
  • A radiotherapist who specializes in radiotherapy
  • A pathologist who specializes in diagnosing sarcomas by looking at body tissue and cells
  • A radiologist who analyses x-rays and scans and is expert in sarcomas

The treatment for sarcomas depends on the size, type, location and stage of the sarcoma, including whether it has spread to the lymph nodes or other parts of the body, and the patient's overall health.

Sarcoma treatments can be divided into local and systemic treatments.

  • Local treatments are surgery and radiotherapy. They treat just one area of the body.
  • Systemic treatments are carried in the bloodstream and can reach cancer cells wherever they are in the body, not just at the original tumor site. Chemotherapy and biological therapies are systemic treatments.

 

Surgery

Surgery is the most common treatment for adult soft tissue sarcoma. For some soft-tissue sarcomas, removal of the tumor in surgery may be the only treatment needed.

Depending on the location and grade of the tumor, surgery may involve:

  • Wide local excision, which involves removing the tumor and a rim, or margin, of normal tissue around the tumor.
  • Amputation to remove all or part of an arm or leg, if resection of the tumor would result in a non-viable limb. Today, advances in surgical techniques and the combination of chemotherapy and radiation before surgery (neo-adjuvant chemo-radiotherapy) or after surgery (adjuvant chemo-radiotherapy) make limb-sparing surgery possible in most cases.
  • Removal of the lymph nodes that are cancerous (lymphadenectomy).
  • Removal of metastatic disease, mainly from the lungs, in special cases (metastasectomy).
  • Isolated limb perfusion method (ILP). At its core ILP is a chemotherapy procedure for treating tumors confined to the arm or leg, but in practice it is a surgical procedure.  It is performed in the operating theater under general anesthesia and takes 3 to 4 hours. Unlike regular systemic chemo, ILP just applies the chemo to the limb.  The limb is isolated from the rest of the bloodstream with a tourniquet.  Since the circulatory system of the limb is isolated from the organs, such as the heart, very high doses of chemo can be used.  The dose is so high that the vascular system of the tumor is attacked and destroyed in a single application.  ILP is a one-time procedure (mostly) and can be applied in cases where amputation seems inevitable. 
  • Plastic surgery. Depending on the size and position of the tumor, the surgeon may have to remove a large area of tissue. Therefore, the patient may need to have some reconstructive/cosmetic (plastic) surgery to repair the area. If this is needed, it will be done at the same time as the operation.

For small, localized sarcomas, surgery is the main treatment and may be curative. It is possible to have radiotherapy afterwards if the surgeon could not completely remove the sarcoma and a wide border of healthy tissue with no cancer cells. The radiotherapy helps to stop the cancer coming back.

If there is a larger tumor that has not spread, it is possible to have radiotherapy or chemotherapy before surgery. This treatment is designed to shrink the sarcoma so that much surgery will not be needed. This is only done with particular types of sarcoma such as rhabdomyosarcoma, osteosarcoma and Ewing’s sarcoma. Some types of sarcoma do not respond so well and are less likely to shrink.

If the sarcoma has spread, for example to the lungs or liver, the treatment may only be able to control it, leading to an improvement in symptoms and a better quality of life. In this case, the patient may undergo surgery to remove the areas of spread. This can help to relieve symptoms and keep the cancer under control for longer.

 

Radiation therapy

Radiation therapy (also called radiotherapy or X-ray therapy) treats cancer by using beams of high-energy particles, such as gamma rays or X-rays. Although radiation can affect healthy cells as well as cancer cells, it is much more harmful to cancer cells. In addition, normal cells can recover from the effects of radiation more easily than cancer cells can.

Radiotherapy can be done before or after surgery for sarcoma, or on its own as the main treatment. Treatment before surgery is called neo-adjuvant treatment. The aim is to shrink the tumor so that it is easier to remove. If the treatment is successful, the patient may be able to have a smaller operation than necessary.

The use of radiotherapy for sarcoma is kept mostly after surgery, to destroy any remaining cancer cells and to reduce the risk of the cancer coming back. This is called adjuvant radiotherapy. The radiotherapy after surgery usually begins between 6 and 12 weeks after the operation. This gives the area time to heal before the radiotherapy starts. Radiotherapy treatment may last for up to 7 weeks. The exact time will depend on the type, size and position of the sarcoma.

Sometimes, radiotherapy may be the main treatment for sarcoma – for example for Ewing’s tumor. In this situation, radiotherapy is used to try to control the sarcoma and slow its growth. Radiotherapy is also given to relieve symptoms and control sarcomas that cannot be removed or has come back since it was first treated.

Newer forms of external beam radiation may be used that can lessen the impact of the radiation on healthy tissue, such as:

  • Intensity modulated radiation therapy (IMRT)
  • Proton beam radiation
  • Carbon-anion radiotherapy

An innovative treatment called intra-operative radiotherapy can be administered in cases where total resection of the tumor could not be faced without provoking major consequences. In this treatment, a computer-controlled robot delivers a rice grain-sized bit of radioactive material to the site of a tumor during surgery, helping reduce damage to normal tissue and organs. The treatment may be performed at the time of the tumor-removing operation.

Side effects from radiation treatment depend on the area being treated, but may include fatigue, skin problems, headache and slower healing after surgery. Radiation to the abdomen may cause nausea, vomiting, and diarrhea, while radiation to the chest may cause pain with swallowing and lung damage leading to problems breathing.

 

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. These drugs enter the bloodstream and reach all areas of the body, making this treatment useful for cancer that has spread to other organs. Depending on the type and stage of sarcoma, chemotherapy may be given in the following ways:

  • Before surgery to shrink the tumor, making it easier to remove. This is known as neo-adjuvant treatment.
  • After surgery to reduce the risk of the cancer coming back. This is called adjuvant treatment. A review of chemotherapy trials in 2008 found that a drug called doxorubicin could lower the risk of sarcoma coming back for some people after surgery. Combining doxorubicin with ifosfamide can lower the risk further but has more side effects. Overall, research in this area suggests that adjuvant chemotherapy is only likely to help people with the highest risk of their sarcoma coming back. This issue is still debatable.
  • To help control symptoms and improve a person’s quality of life if the cancer cannot be removed or has spread to other parts of the body. This is called palliative treatment.

Chemotherapy for soft tissue sarcoma generally uses a combination of several anti-cancer drugs. The most commonly used drugs for soft tissue sarcomas are:

  • Doxorubicin
  • Ifosfamide

Other drugs which may be used include:

  • Trabectedin
  • Dacarbazine
  • Gemcitabine
  • Docetaxel
  • Paclitaxel

These drugs can be given as monotherapy, or two or more may be given together in combination.

Chemotherapy is given as a session (or cycle) of treatment. It may be given as an outpatient or may need to be admitted to hospital for a few days. Treatments for sarcoma can be given weekly or every 2, 3 or 4 weeks, depending on the drugs and the treatment plan.

Possible side effects from chemotherapy include nausea, vomiting, hair loss, mouth sores, fatigue, increased risk of infection, weakness, and increased bleeding and fertility problems.

 

Targeted therapy

Targeted or biological therapies are treatments that work by targeting specific proteins that are found either on the surface of cells or within the cell itself. They include cancer growth inhibitors and monoclonal antibodies.

Some of them are:

  • Imatinib for first-line treatment of GIST and for dermatofibrosarcoma protuberans
  • Sunitinib for second-line treatment of GIST
  • Regorafenib for third-line treatment of GIST
  • Pazopanib for all types of sarcomas, except, mainly, liposarcomas
  • Denosumab for giant-cell tumor of the bone

 

Specific subtypes may benefit from agents outside the typical approach of anthracyclines and alkylators (e.g., taxanes for angiosarcoma and trabectedin for myxoid/round cell liposarcomas.

The heterogeneity of diagnoses as well as different patient’s ages does not help to formulate a guide on systemic treatment, and clear guidelines cannot be standardized. This is particularly noticed beyond first-line treatment where the available agents have similar efficacy and the short median survival of these patients does not always allow for multiple treatment attempts. By subgrouping sarcoma patients with new molecular techniques, novel approaches and regimens will be developed and a personalized treatment will be given.

The participation of a sarcoma patient in research clinical trials is encouraged, especially in advanced stage where the general prognosis is not optimal. Trials are the only reliable way to confirm the value of a different operation, type of chemotherapy, radiotherapy or other treatment in comparison with the existing ones. A cancer specialist will be able to provide more information about these trials.

 

Follow-up

The schedule of follow up begins with the end of treatment. Usually, this means visits with some type of imaging and/or other ancillary testing (cardiac testing, laboratory exams, etc.) every three to four months for 2-3 years, every 6 months until 5 years after treatment, then annually.

In some cases, depending on potential risk of returning the sarcoma, these schedules are varied. The majority of recurrences will be appeared in the first two to three years. Afterwards the risk of recurrence is reduced, but still exists. Finally, the recognition of long-term toxicities of treatments that have been used is important.

 

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