Childhood rhabdomyosarcoma is a soft tissue cancer that arises in the muscles. It accounts for 3 to 4 percent of all cases of childhood cancer and for nearly 50 percent of all childhood soft tissue sarcomas.

Rhabdomyosarcoma can start in any muscle in the body, and tumor origin is often associated with age. Most head and neck tumors occur in children younger than age 8, whereas tumors in the arms and legs are most commonly diagnosed in adolescents. Rhabdomyosarcoma is also found in the genitourinary tract, including the bladder, prostate, and vagina.

There are two distinct subtypes of rhabdomyosarcoma. In the past, these subtypes were defined exclusively by how the tumors looked under the microscope, but today the presence or absence of a specific genetic mutation is considered the most accurate way of identifying the two subtypes. The mutation is a translocation—a genetic accident that results in a piece of one gene (called PAX) getting stuck next to a piece of another gene (called FOXO1), creating a new cancer gene that is only found in the tumor cells. The subtypes are:

•  Embryonal (also called ERMS). This type accounts for 70 to 80 percent of all childhood rhabdomyosarcomas. Tumors with this histology usually arise in the head, neck, and genitourinary areas. Botryoid and spindle cell tumors are subtypes of embryonal tumors accounting for about 10 percent of rhabdomyosarcoma diagnoses, and they are most often diagnosed in very young children. Botryoid tumors are found under the mucosa (moist tissues) of the vagina, bladder, or nasopharynx (space between the back of the nose and the top of the mouth). Spindle cell tumors most often occur in the tissues around the testes (called the paratesticular area) in boys. These tumors do not contain the PAX-FOXO1 translocation.

•  Alveolar (also called ARMS). Approximately 20 percent of rhabdomyosarcoma tumors have alveolar histology. These tumors are a more aggressive form of rhabdomyosarcoma. Alveolar rhabdomyosarcoma is found more frequently in adolescents and in children with tumors of the trunk, limbs, anus, scrotum (in boys), or external genital area (in girls). These tumors always contain the PAX-FOXO1 translocation, although there are two different variants of this translocation.

Who gets rhabdomyosarcoma?

Rhabdomyosarcoma is the most common childhood soft tissue sarcoma. Approximately 400 children and adolescents are diagnosed with rhabdomyosarcoma in the United States each year, and half of them are younger than age 6. The disease has a slightly higher incidence in males than in females. The occurrence of disease found in White and Black males is very similar; however, the incidence in Black females is only half of that in White females.

Genetic factors

The cause of rhabdomyosarcoma is not known, but it is associated with some other conditions. For example, children with Li-Fraumeni syndrome, neurofibromatosis, or Beckwith-Wiedemann syndrome have a higher chance of developing rhabdomyosarcoma than children without them.

Staging

Once rhabdomyosarcoma has been diagnosed through surgical biopsy and microscopic analysis of the tissue, more tests are done to determine whether the cancer has spread to other parts of the body. Computerized tomography (CT), magnetic resonance imaging (MRI), and nuclear bone scans are used to evaluate the extent of the disease and to see whether the tumor has spread. Many hospitals now do positron emission tomography (PET) scans instead of bone scans.

The most common sites that rhabdomyosarcoma spreads to are the lungs, nearby lymph nodes, lymph nodes in other parts of the body, bones in other parts of the body, and bone marrow. To check to see if the disease has spread to any of these locations, doctors do additional procedures. For example, a bone marrow aspiration and biopsy may be performed to see whether the disease has spread to the bone marrow. For tumors located in the sinuses or at the base of the skull, a spinal tap is done to see whether tumor cells have spread to the lining of the brain. If the mass is located in the pelvic area, ultrasonography may be done along with the CT scan. This process is called staging, and it helps the doctor choose the most appropriate treatment for the child.

The staging of rhabdomyosarcoma involves three steps.

Step 1: Assigning a stage. The stage is determined by the location of the tumor (also known as the primary site), its size, the extent of nearby lymph node involvement, and whether the tumor has metastasized (spread to distant sites in the body). Primary sites are divided into two groups—favorable and unfavorable.

•  Stage 1. The tumor is in a favorable site: this includes the orbits, eyelids, head (excluding the parameningeal area of the middle ear, nasal cavity, and sinuses), neck, gall bladder, bile ducts, or the genitourinary region (excluding the kidney, bladder, and prostate). Tumor cells may be present in nearby lymph nodes, but have not spread to other parts of the body.

•  Stage 2. The tumor is in an unfavorable location, such as the sinuses, nasal cavity, extremities, bladder, prostate, perineum (in boys, area between the anus and scrotum; in girls, the area between the anus and vagina), chest wall, or around the spine. Primary tumors must be less than or equal to 5 centimeters (cm) in diameter and nearby lymph nodes cannot contain tumor cells. No distant metastases are present.

•  Stage 3. The tumor is in an unfavorable site and is either more than 5 cm, or any size with nearby lymph node involvement. No distant metastases are found.

•  Stage 4. The tumor has spread to distant sites.

Step 2: Assigning a surgical-pathologic group.

•  Group I. A tumor is completely removed, no disease is found in the tissue taken from around the tumor (called margins), and lymph nodes in the region do not contain any tumor cells. No distant metastases are found.

•  Group II. A tumor is completely removed but either microscopic disease has been detected in the margins or disease is found in nearby surgically removed lymph nodes. No distant metastases are found.

•  Group III. A tumor could not be completely removed during surgery. This is the most common tumor group. No distant metastases are found.

•  Group IV. Distant metastases are present at diagnosis.

Step 3: Assigning a risk group.

•  Low risk. Children are considered to have low-risk disease if their stage and group are: (1) embryonal histology Stage 1 and Group I, II, or III; or (2) embryonal histology Stage 2 or 3 and Group I or II.

•  Intermediate risk. Children are considered to have intermediate-risk disease if their stage and group are: (1) histology Stage 2 or Stage 3 and Group III; or (2) alveolar histology Stage 1, 2, or 3 and Group I, II, or III.

•  High risk. Children are considered to have high-risk disease if their stage and group are embryonal or alveolar Stage 4 and Group IV.

Prognosis

Since the 1970s, the treatment of rhabdomyosarcoma has dramatically improved. A child’s prognosis is determined through the analysis of several clinical and biological features. For tumors that have not spread to other parts of the body (Stages 1, 2, and 3), the most important risk factor is the presence or absence of the PAX-FOXO1 translocation. Children or teens who have tumors that are completely resected (removed) often have the best prognoses.

Treatment of rhabdomyosarcoma

At diagnosis, many parents do not know how to find experienced doctors and the best treatments for their child. State-of-the-art care is available from physicians who participate in the Children’s Oncology Group (COG). This study group includes pediatric surgeons and oncologists, radiation oncologists, researchers, and nurses. COG conducts studies to discover better therapies and supportive care for children with cancer. You can learn more about COG and find a list of its member treatment centers at www.childrensoncologygroup.org.

A pediatric oncologist will explain the child’s treatment options: a standard treatment or a clinical trial, if open (see Chapter 9, Choosing a Treatment). For children and teens with rhabdomyosarcoma, treatment can include surgery, chemotherapy, and radiation.

Surgery

All children diagnosed with rhabdomyosarcoma will have some type of operation to determine the diagnosis. This may be a needle biopsy or small incisional biopsy, or it may be a larger operation that removes some or all of the primary tumor. An experienced pediatric surgeon who has extensive experience with the treatment of pediatric sarcomas should perform any biopsy or surgery.

Surgery usually happens very early in the course of treatment because it can reduce the amount of the disease. However, the tumor may not be completely removed if it is located near vital blood vessels, if it invades surrounding normal tissue, or if its removal will have a significant functional or cosmetic effect.

During surgery, the pediatric surgeon removes some or all of the tumor and then may sample surrounding tissues that are later examined by a pathologist (doctor who examines tissues under a microscope). The pathologist looks at the margins (tissue around the tumor that is removed during surgery) and determines whether the entire tumor has been removed, or whether some cancer cells remain. If the surgeon is able to remove the entire tumor, it is referred to as a gross total resection. If there is evidence of remaining disease, it is referred to as residual disease. If the surgeon can see or feel remaining tumor, the tumor that could not be surgically removed is called gross residual disease. If tumor cells in the margins are only visible under the microscope, it is called microscopic residual disease.

Approximately 15 percent of newly diagnosed children have tumors that can be completely removed. In the other 85 percent of children, some disease remains after surgery. As a result, chemotherapy is used in all treatment protocols, and radiation is used in most. Second-look surgical procedures, done after a period of chemotherapy, are sometimes recommended to remove any remaining residual disease and to determine whether further treatment is necessary. For more information, see Chapter 14, Surgery.

Chemotherapy

All children diagnosed with rhabdomyosarcoma receive chemotherapy to kill tumor cells that remain after surgery. Giving several chemotherapy drugs in combination has markedly improved the survival rate for this disease. The most commonly used drugs include vincristine, dactinomycin, cyclophosphamide, ifosfamide, etoposide, doxorubicin, and irinotecan. For information on these drugs, see Chapter 15, Chemotherapy.

Radiation therapy

Radiation therapy is an important tool used to treat children with rhabdomyosarcoma. Radiation is a form of energy that can be passed from a machine through the air and into a child’s body. It is used to kill tumor cells that remain following surgery and chemotherapy. Radiation may also be given in the operating room during surgery (intraoperative radiation therapy) or with seed implants (brachytherapy).

Three main types of energy beams are used: electrons, photons, or protons. Electrons tend to be used for superficial tumors, and photons or protons are usually used for deep-seated tumors. Proton-beam radiation may be recommended for very young children or for tumors at the skull base or in the pelvis to try to minimize the risk of radiation damage to surrounding tissues. Recommendations for radiation therapy depend on the site of the primary tumor and on the amount of tumor left after surgery.

The 15 percent of children whose tumors are completely removed (Stage 1, Group I) do not usually receive radiation treatments. The 85 percent of children who have residual disease after surgery are usually treated with radiation to the primary tumor site. Most protocols call for radiation therapy to begin 6 to 12 weeks after the first doses of chemotherapy are given; however, children with Stage 4 rhabdomyosarcoma often have radiation delayed until 22 to 24 weeks after the start of chemotherapy.

Children with residual disease receive doses of 180 to 200 centigray (cGy) of external beam radiation a day for up to 6 weeks. The total amount of radiation given to the prechemotherapy tumor site may reach 3,600 to 5,040 cGy.

A child or teen receiving radiation therapy must be completely still so the radiation beam is aimed at the right spot. Young children may require daily anesthesia so they can safely receive radiation therapy. For more information, see Chapter 17, Radiation Therapy.