Soft Tissue Sarcoma

What is Soft Tissue Sarcoma?

Soft tissue sarcoma is a type of cancer that grows in the body’s soft connective tissue including muscle, nerves, tendons, fat, and walls of blood and lymph vessels. Soft tissue sarcomas can be divided into two main types:

Rhabdomyosarcoma
Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)

Soft tissue sarcomas account for about 7% of all childhood cancers. Rhabdomyosarcoma is more common in younger children, and NRSTS is more common in adolescents. The clinical behavior of soft tissue sarcomas can range from locally aggressive to highly metastatic.

Soft tissue sarcomas are named for the tissue which they most resemble:

Skeletal muscle: rhabdomyosarcoma
Smooth muscle: leiomyosarcoma
Cartilage: chondrosarcoma
Synovium: synovial sarcoma
Fat: liposarcoma
Blood and lymph vessels: angiosarcoma
Peripheral nerves: malignant peripheral nerve sheath tumor
Fibrous tissue: fibrosarcoma

Certain inherited conditions can increase risk for soft tissue sarcomas. Children who have been exposed to ionizing radiation are also at higher risk. Treatment for soft tissue sarcoma usually includes surgery, chemotherapy, and/or radiation therapy.

In this microscope image of a rhabdomyosarcoma tumor in situ, immature, tumor-forming cells appear red are shown lining the blood vessels forming tumors between the muscle fibers which appear green. — Rhabdomyosarcoma

Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. Until recently, scientists thought that rhabdomyosarcoma grew from immature muscle cells. This is because the tumor cells look like muscle cells under a microscope. However, new research shows that rhabdomyosarcoma can actually grow from immature endothelial cells, cells that would normally develop to line blood vessels.

Drummond CJ, Hanna JA, Garcia MR, Devine DJ, Heyrana AJ, Finkelstein D, Rehg JE, Hatley ME. Hedgehog Pathway Drives Fusion-Negative Rhabdomyosarcoma Initiated From Non-myogenic Endothelial Progenitors. Cancer Cell. 2018 Jan 8;33(1):108-124.e5. https://www.cell.com/cancer-cell/abstract/S1535-6108(17)30524-X. doi: 10.1016/j.ccell.2017.12.001.

What is Rhabdomyosarcoma?

Rhabdomyosarcoma is a type of soft tissue tumor that often develops in muscle. However, it can form anywhere in the body and is the most common pediatric soft tissue sarcoma. It usually affects children under 10 years of age and can develop before birth.

There are two types of rhabdomyosarcoma:

Embryonal rhabdomyosarcoma – This tumor is most common in children under 5 years of age and often forms within the head, neck, bladder, vagina, prostate or testicles.
Alveolar rhabdomyosarcoma – This tumor affects all age groups and usually forms in the larger muscles of the arms, legs, and trunk of the body.

Risk Factors and Causes of Rhabdomyosarcoma

Certain factors may increase risk for rhabdomyosarcoma including age, gender, and ethnicity.

About 2/3 of rhabdomyosarcoma tumors are diagnosed in children under 10 years old.
Rhabdomyosarcoma occurs slightly more often in males than females.
Caucasian children have a higher risk of rhabdomyosarcoma compared to African-American children.
Certain inherited conditions can increase risk for rhabdomyosarcoma including Li Fraumeni syndrome (P53 mutations), DICER1 mutations, Neurofibromatosis type 1 (NF1), Costello syndrome, Beckwith Weidemann syndrome, and Noonan syndrome.

Signs and Symptoms of Rhabdomyosarcoma

Symptoms of rhabdomyosarcoma depend on where the tumor is located. Signs and symptoms of rhabdomyosarcoma include:

Swelling or a lump that does not go away, sometimes painful
Headaches
Bulging of the eye
Bleeding in the nose, vagina, or rectum
Constipation or difficulty urinating

Diagnosis of Rhabdomyosarcoma

Several types of procedures and tests are used to diagnose rhabdomyosarcoma. These include:

A health history, physical exam, and blood test to learn about symptoms, general health, past illnesses, and risk factors.
Imaging tests including MRI, CT scan, and/or ultrasound to evaluate the primary tumor determine other tests that are needed.
- An MRI is used to evaluate the primary tumor.
- A CT scan of the chest is used to see if rhabdomyosarcoma has spread to the lungs. If the tumor is in the lower part of the body, a CT scan of the abdomen and pelvis may be needed.
- Full body imaging using bone scans or PET scans is used to look for cancer in bone and other areas of the body.
Bone marrow aspiration and biopsy to see if cancer has spread. Doctors will obtain bone marrow sample by inserting a thin, hollow needle into the hipbone. A pathologist will view the bone marrow under a microscope to look for signs of cancer.
A biopsy of the tumor to make a diagnosis. In a biopsy, the doctor removes a small amount of tissue from the tumor. The cells are then examined with a microscope to look for signs of cancer. An incisional biopsy or core needle biopsy may be used depending on tumor location.

Depending on the location of the tumor, additional tests may be needed including:

Sentinel lymph node biopsy to examine spread of rhabdomyosarcoma to nearby lymph nodes. In this procedure, a special dye or radioactive substance is injected near the tumor. The dye travels through the lymph system to the first lymph nodes near the primary tumor. Those lymph nodes can be removed and evaluated for signs of cancer. This is important to determine stage of rhabdomyosarcoma and help in planning treatments.
A lumbar puncture to look for cancer cells in the cerebrospinal fluid in the case of tumors that occur near the membranes of the brain and spinal cord (parameningeal).

Site-specific evaluations may be needed depending on tumor location. A multidisciplinary medical team is important to provide optimal care throughout treatment.

MRI of pediatric rhabdomyosarcoma patient's forearm with tumor marked — MRI of pediatric rhabdomyosarcoma patient's forearm

MRI of pediatric rhabdomyosarcoma patient's abdomen with tumor marked — MRI of rhabdomyosarcoma patient's abdomen

MRI of pediatric rhabdomyosarcoma patient's abdomen from a cross section, or axial view. — MRI of pediatric rhabdomyosarcoma patient's abdomen from a cross section, or axial, view

Staging of Rhabdomyosarcoma

In rhabdomyosarcoma, there are different ways the disease can be classified. This can help doctors better understand the disease and plan appropriate treatments.

Rhabdomyosarcoma is grouped based on tumor location, spread of disease, and result of surgery.

Group	Spread of disease
Group I No disease after surgery	The tumor is limited to one area and is completely removed with surgery.
Group II Microscopic disease after surgery	The tumor is limited to one area and is removed with surgery, but cancer cells are found in nearby tissue that surrounded the tumor (margin) and/or lymph nodes.
Group III Significant disease after surgery	The tumor is limited to one area but cannot be completely removed with surgery.
Group IV Metastatic disease	The tumor has spread to other parts of the body at diagnosis (metastatic).

Rhabdomyosarcoma can also be staged using the TNM system. This system considers 3 factors:

Tumor (T) – Size and location of the primary tumor
Node (N) – Spread of disease to lymph nodes
Metastasis (M) – Spread of disease to other parts of the body

Using the TNM System, rhabdomyosarcoma can be divided into 4 stages.

Stage	Location	Tumor Size	Lymph Nodes	Metastasis
	Where is the primary tumor?	How large is the tumor?	Are cancer cells found in nearby lymph nodes?	Has the cancer spread to other parts of the body?
1	Favorable: Tumor is in the area of the eye, head or neck or in the genitorurinary tract Exceptions: Tumor is located near the brain or spinal cord or in the bladder or prostate	Any size	Yes or No	No
2	Unfavorable: All other sites	Less than 5 cm	No	No
3	Unfavorable: All other sites	Less than 5 cm Greater than 5 cm	Yes Yes or No	No
4	Any site	Any size	Yes or No	Yes

Prognosis for Rhabdomyosarcoma

The chance of recovery from rhabdomyosarcoma depends on several factors:

Size and location of the tumor
- Larger tumors (greater than 5 centimeters) are more difficult to treat.
- Some tumors have a better prognosis based on location. Tumors are considered favorable (higher chance of cure) when they are located in the following places in the body:
  - Eye area (orbit)
  - Head and neck (except if they are near the membranes of the brain or spinal cord)
  - Genital or urinary tract (except in the bladder or prostate)
  - Bile ducts
Patient age (younger and older patients tend to do worse)
Type of rhabdomyosarcoma: Embryonal tumors tend to have a better outcome compared to alveolar tumors.
Whether the cancer has spread to lymph nodes or other parts of the body (metastatic disease)
The ability of surgery to completely remove the tumor

Risk Groups

Doctors classify rhabdomyosarcoma patients into risk groups to help plan treatments. Groups are based on the stage of disease and the ability of surgery to remove the tumor.

Low Risk – Patients are classified as low risk if they have an embryonal tumor that can be completely removed with surgery.
Intermediate Risk – Patients are classified as intermediate or medium risk if they have:
- An embryonal tumor that is not completely removed with surgery, or
- An alveolar tumor that has not spread to distant parts of the body.
High Risk – Patients are classified as high risk if they have Stage 4 or metastatic disease.

This information helps doctors decide what treatments to use, dose of medication, and the number of treatments needed.

If rhabdomyosarcoma has recurred, prognosis may be influenced by where in the body the cancer came back, how much time passed between the original cancer and recurrence, and what therapies were originally used to treat the cancer.

Children with localized rhabdomyosarcoma have greater than 70% chance of long term cure. About 20% of patients have metastatic disease at diagnosis. If the cancer has already spread at diagnosis (metastatic rhabdomyosarcoma), the chance of survival is less than 30%.

Approximately 30% of patients with rhabdomyosarcoma will have recurrence of cancer. Rhabdomyosarcoma may recur at the location of the initial tumor or in other sites. Recurrent rhabdomyosarcoma is difficult to treat, and the chance of cure is low.

Treatment of Rhabdomyosarcoma

Rhabdomyosarcoma requires a combination of treatments including chemotherapy, surgery, and/or radiation therapy. All children receive systemic chemotherapy as part of treatment for rhabdomyosarcoma. This is important to treat microscopic spread of disease that may not be detected. Tumors visible on imaging are also treated with surgery and/or radiation therapy.

Surgery is used to remove the cancer when possible. A small amount of tissue around the tumor and nearby lymph nodes are also removed. Because rhabdomyosarcoma can occur anywhere in the body, each surgery is different. Patients are treated with chemotherapy after surgery to kill any remaining cancer.
Chemotherapy (“chemo”) is uses powerful medicines to kill cancer cells or stop them from growing and making new cancer cells. Often, more than one type of medicine will be used to treat the cancer. Most chemotherapy is given through injections but some chemo may be given by mouth. Chemotherapy may be given before surgery to make the tumor smaller. Chemotherapy is given after surgery to kill any remaining cancer cells and to help keep the tumor from coming back.

The chemotherapy regimen for rhabdomyosarcoma includes vincristine, actinomycin D, and cyclophosphamide and irinotecan. A standard course of treatment is 14-16 cycles (period of treatment followed by period of rest).

Radiation therapy may be used to treat rhabdomyosarcoma in combination with chemotherapy and/or surgery. Radiation uses high energy particles to kill or stop the growth of cancer cells. Radiation therapy is the main treatment for metastatic disease in rhabdomyosarcoma.

Other treatments include other chemotherapy drugs like doxorubicin and experimental agents such as targeted therapies, drugs that inhibit the cell cycle, and immunotherapy.

Many children are offered treatment for rhabdomyosarcoma as part of a clinical trial.

Targeted therapies are newer drugs that act on specific targets of cancer cells to stop them from growing. Kinase inhibitors and monoclonal antibodies are being studied in the treatment of rhabdomysarcoma. Kinase inhibitors act to block a protein that signals cancer cells to grow. Monoclonal antibody therapy uses special proteins that attach to cancer cells to kill the cells or slow cell growth.

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a group of tumors that develop in soft tissues of the body. Although there are many types of NRSTS, they are usually treated in a similar way.

NRSTS account for about 4% of all childhood cancers. They are most common in adolescents. There are about 500-600 patients diagnosed with NRSTS in the United States each year.

NRSTS can form anywhere in the body but are most often found in the arms and legs. NRSTS can also occur in the head and neck, chest, abdomen, and pelvis.

The most common types of NRSTS in children include:

Fibrosarcoma
Synovial sarcoma
Malignant peripheral nerve sheath tumors

Other types of NRSTS are clear cell sarcoma, epithelioid sarcoma, hemangiopericytoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, non-synovial cell sarcoma and undifferentiated sarcoma.

Risk Factors and Causes of NRSTS

NRSTS in children are most often seen in two age groups: infants and adolescents. They occur slightly more often in males. Previous treatment with radiation therapy can also increase risk for NRSTS.

Certain inherited conditions can increase risk for rhabdomyosarcoma. These include Li-Fraumeni syndrome (P53 mutations), Neurofibromatosis type 1 (NF1), familial adenomatous polyposis (FAP), Werner syndrome, Retinoblastoma 1 (RB1) gene changes, and SMARCB1 (INI1) gene changes.

Signs and Symptoms of NRSTS

Symptoms of NRSTS depend on where the tumor is located. Often there are no symptoms in the early stages other than a painless lump. Problems such as pain or weakness may develop as the tumor grows and presses on other structures. More advanced disease can sometimes produce symptoms such as fever, sweating, or weight loss.

Diagnosis of NRSTS

Several types of procedures and tests are used to diagnose rhabdomyosarcoma. These include:

A health history, physical exam, and blood tests to learn about symptoms, general health, past illnesses, and risk factors.
Imaging tests including MRI or CT scan to evaluate the primary tumor.
A biopsy of the tumor to make a diagnosis. In a biopsy, the doctor removes a small amount of tissue from the tumor. The cells are then examined with a microscope to look for signs of cancer. An incisional biopsy or core needle biopsy may be used depending on tumor location.
If there are concerns about metastatic disease, a CT scan of the chest is used to see if sarcoma has spread to the lungs. Full body imaging using bone scans or PET scans is used to look for metastatic cancer in bone and other areas of the body. Imaging and biopsy of lymph nodes may also be performed.

Staging of NRSTS

Soft tissue sarcomas are classified by stage. Staging is based on features of the tumor such as size, whether it has spread, and grade of the tumor.

Grade refers to the way cancer cells look under the microscope. The grade helps predict how likely the cancer is to spread. Higher grade tumors tend to grow and spread faster compared to lower grade tumors.

For soft tissue sarcoma, tumor grade is based on 3 factors: differentiation, mitotic count, and necrosis.

Differentiation (1-3): This refers to how different from normal the cells look. A higher score means that cells look very abnormal under a microscope.
Mitotic count (1-3): This is a measure of how many tumor cells are dividing when viewed under a microscope. A higher score means that there are more dividing cells.
Tumor necrosis (0-2): This is a measure of how much of the tumor is made up of dead or dying cells. A higher score means that more dying tissue is present.

Each factor is given a score. The higher the total score, the higher the tumor grade.

Soft tissue sarcomas can be grouped into four stages. The American Joint Committee on Cancer (AJCC) uses the following criteria:

Stage	Description	Tumor Grade
Stage IA	The tumor is no larger than 5 centimeters across. It has not spread to lymph nodes or other parts of the body.	1
Stage IB	The tumor is larger than 5 centimeters across. It has not spread to lymph nodes or other parts of the body.	1
Stage IIA	The tumor is no larger than 5 centimeters across. It has not spread to lymph nodes or other parts of the body.	2 or 3
Stage IIIA	The tumor is 5-10 centimeters across. It has not spread to lymph nodes or other parts of the body.	2 or 3
Stage IIIB	The tumor is greater than 10 centimeters across. It has not spread to lymph nodes or other parts of the body.	2 or 3
Stage IV	The tumor is any size and any grade. It has spread to nearby lymph nodes and/or other parts of the body.	Any

Prognosis for NRSTS

The prognosis, or chance of recovery, from NRSTS depends on several factors:

Type of tumor
Where the tumor formed in the body
Tumor grade and how the cells look under a microscope (histology); low grade tumors have a better prognosis
Size of the tumor - larger tumors (greater than 5 centimeters) are harder to treat
How deep the tumor is located below the skin
Whether the cancer has spread to lymph nodes or other parts of the body (metastatic disease)
Whether surgery can completely remove the tumor
Whether the tumor is new or has come back (recurrent)
Whether radiation has been used to treat the cancer

Patients with a favorable tumor that meets certain conditions have a better prognosis:

	Favorable	Unfavorable
Tumor grade (histology)	Low grade	High grade
Tumor size	Less than 5 cm	Greater then 5 cm
Spread of disease (metastatic)	No	Yes
Complete removal with surgery	Yes	No

About 15% of patients have metastatic disease at diagnosis. The lung is the most common site for metastasis of NRSTS. Rarely, NRSTS may spread to bone or lymph nodes.

If the cancer has already spread at diagnosis (metastatic disease), the chance of long-term survival is less than 20%.

Recurrent NRSTS is difficult to treat, and the chance of cure is low.

Treatment of NRSTS

Surgery is used to remove as much of the cancer as possible. A small amount of tissue around the tumor and nearby lymph nodes are also removed to make sure that no cancer is left behind. Low risk patients may be treated with surgery alone if the tumor can be fully removed with no remaining cancer cells.

Radiation therapy may be used to treat NRSTS that cannot be removed completely with surgery. In some cases, radiation may be used before surgery to make the tumor easier to remove.

Chemotherapy (“chemo”) uses powerful medicines to kill cancer cells or stop them from growing and making new cancer cells. Chemotherapy is not as effective for NRSTS. It is most often used to treat high risk patients including those with metastatic disease or patients who cannot be treated with surgery.

Targeted therapies

Targeted therapies are being studied in the treatment of NRSTS. These drugs act on specific targets of cancer cells to stop them from growing. Certain therapies are specific for subtypes of NRSTS. Many of these treatments are being studied in clinical trials.

Tumor Subtype	Drug	Action
Adipocytic Liposarcoma	Palbiciclib	kinase inhibitor
Alveloar soft part sarcoma	Sunitinib	kinase inhibitor
Perivascular epitheloid cell tumors (PEComa)	Sirolimus	mTOR inhibitor
Inflammatory myofibroblastic tumor	Crizotinib Ceritinib	kinase inhibitor

Young rhabdomyosarcoma patient kneels, talking with a golfer at a tournament

"Two years off therapy, we are cancer free but still not at the 5-year mark. As time passes, I find that my worries change. The stress of cancer is still there. 'Scanxiety' hits as our 6-month checkup time gets closer. But what I look for now are more post-therapy effects, especially related to proton beam radiation because it just hasn’t been around long enough to know what to expect."

– Michelle, mom to Reid

Reid was treated for two rare cancers behind his eye: rhabdomyosarcoma and ectomesenchymoma. His treatments included surgery, chemotherapy, and proton beam radiation.

Life after Soft Tissue Sarcoma

Monitoring for Recurrence

Soft tissue sarcomas can recur years into survivorship. The tumor can come back in the same place (local recurrence) or in another part of the body (distant recurrence).

Patients will receive follow-up care to screen for recurrence after treatment ends. The medical team will make specific recommendations for the types of tests needed and how often patients should be seen for checkups.

Health after Cancer

Children treated for soft tissue sarcoma are at risk for late effects related to therapy. Specific problems depend on the location of the tumor and the type of therapy received.

Long-term effects of surgery can include loss of function and changes in appearance.

Survivors treated with radiation therapy may have impaired growth, bone disease, and other problems due to treatment as well as increased risk of second cancers.

Survivors treated with systemic chemotherapy should be monitored for medication-specific late-effects which may include heart problems, kidney damage, infertility, endocrine dysfunction, and risk of second cancers.

All survivors should continue to have regular physical checkups and screenings by a primary physician. For general health and disease prevention, survivors should adopt healthy lifestyle and eating habits.

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Reviewed: June 2018