What is a sarcoma?

Sarcoma is a general medical term that refers to any cancer of the bone, muscle, or other connective tissue, such as cartilage and tendons. Sarcoma has sometimes been defined as a "tumor of fleshy consistence", made up of cells similar to those of the growing fetus, but without proper development.

Sarcomas can occur in both children and adults, both males and females. In fact, there are many different types of sarcomas, depending on where the cancer cells grow and how they appear under a microscope. These different types are in turn associated with different clinical behavior, which naturally influences how they are treated.

What is a rhabdomyosarcoma?

Rhabdomyosarcoma is the most common type of soft tissue sarcoma found in children. It is still a rare cancer overall, accounting for about 3.5% of all childhood cancers. About 250 new cases of rhabdomyosarcoma are diagnosed in the United States every year.

The name itself comes from a combination of 3 smaller words: rhabdo means "rod-shaped", myo is muscle, and sarcoma is the type of cancer, as described above. Rhabdomysarcoma cells tend to look rod-shaped under a microscope, and they have several features of muscle cells. Normally, as a fetus develops in the womb, cells called rhabdomyoblasts "grow up" to become the skeletal muscles of the body. When these cells do not mature correctly, but continue to multiply abnormally, a rhabdomyosarcoma results. Rhabdomyosarcomas can occur essentially anywhere in the body, but usually occur in the head, neck, bladder, vagina, extremities and the trunk.

Who gets rhabdomyosarcomas, and why?

Over 85% of all rhabdomyosarcomas occur in infants, children, and teenagers. There is no specific geographic location or racial background that has been associated with higher rates of rhabdomyosarcoma. However, Asian and black children have a lower annual incidence than do white children. There also appears to be a male predominance, as boys are about 1.5 times more likely than girls to get rhabdomyosarcoma.

It is known that rhabdomyosarcomas are associated with specific chromosomal abnormalities. The exact cause of these mutations, however, is not known. Some children who develop rhabdomyosarcomas also have congenital anomalies of various organ systems (abnormal development of heart, gut, brain, etc). The risk of rhabdomyosarcoma may be elevated for children who also have certain rare genetic disorders, such as neurofibromatosis type 1. Unlike many adult cancers, there are no known definitive environmental conditions that increase the chance of a person developing rhabdomyosarcoma. No connection has ever been found between rhabdomyosarcoma and exposure to toxic substances, environmental pollution, radiation (eg: x-rays during pregnancy), or physical injury (trauma). Not even tobacco smoke has been linked with development of this or any other childhood cancers, although cigarette smoke is clearly and certainly harmful to children in many other ways.

Are all rhabdomyosarcomas the same?

No. Just as there are different types of sarcomas, there are different types of rhabdomyosarcomas, as well. The 2 major types of rhabdomyosarcomas are described below. The classification is based on unique microscopic appearance, genetic mutations, and clinical behavior.

Embryonal rhabdomyosarcoma

This is the most common type of rhabdomyosarcoma. It tends to occur in the head and neck, bladder, vagina in girls, and around the prostrate and testes in boys. This type usually affects infants and young children. As the name implies, the cells, as the name implies, have an "embryo-like" appearance, meaning they resemble the developing muscle cells of a 6- to 8-week-old fetus. Embryonal rhabdomyosarcomas have a relatively good to intermediate prognosis depending on other individual aspects of the disease.

Alveolar rhabdomyosarcoma

This type is found more often in large muscles of the trunk, arms, and legs, and typically affects older children or teenagers. It is called alveolar because the cancer cells form little hollow spaces, or "alveoli" (Latin for small hollow spaces). Alveolar rhabdomyosarcoma cells resemble the normal muscle cells seen in a 10-week-old fetus. Most alveolar rhabdomyosarcomas have specific genetic mutation, called a 2;13 translocation. Tumor tissue is usually tested for this mutation before a diagnosis of alveolar disease is made. Alveolar rhabdomyosarcomas may be more aggressive than embryonal tumors, and their treatment may be longer and more intense. Again, this depends on individual disease aspects as well as the tumor diagnosis.

How do rhabdomyosarcomas present?

The answer to this question really depends on the location of the tumor. As mentioned earlier, rhabdomyosarcomas can arise from any skeletal muscle in the body, but the most common sites are the head and neck region, the genitourinary organs (GU), and the extremities.

Tumors in the head and/or neck region can cause headaches, nausea, vomiting, visual problems (double vision), facial drooping, and airway obstruction, among other things.

Tumors in the GU area can cause blockage of the bladder or bowels, which can be a medical emergency depending on the degree of obstruction.

Growths on the extremities can be painful and limit the use and motion of the affected arm or leg.

Sometimes, the rhabdomyosarcoma is not diagnosed until after the tumor cells have spread to other parts of the body. The most common areas they spread to are the lungs, bones, bone marrow, and lymph nodes.

How are rhabdomyosarcomas evaluated?

The workup of these tumors typically includes the following studies:

• CT and MRI scans of affected region(s)
• CXR or CT scan of chest
• Bone scan
• Bone marrow biopsy
• For GU location:
  • Cystoscopy (scope to look inside the bladder)
  • Barium enema and rectal ultrasound

How are rhabdomyosarcomas staged?

The staging system for rhabdomyosarcoma is very complicated. All rhabdomyosarcomas are assigned a group, a stage, and a risk category.

In order for stage to be assigned, the disease must be determined to be in either a "favorable" or an "unfavorable" site. Favorable sites include:

• Non-parameningeal head & neck: This includes all sites within the head and neck that do not touch the meninges, or the tissue that surrounds the brain and spinal cord.
• Orbit
• Biliary tract
• Vagina
• Paratesticular region

All other sites of disease are classified as "unfavorable."

Group assignments are made based on the amount of tumor, if any, that is removed surgically.

• Group I = Localized disease, completely resected (removed surgically)
• Group II = The tumor is removed surgically, but there are either microscopic cells left behind (2a) or microscopic cells seen in the lymph nodes (2b)
• Group III = The tumor is localized and has been biopsied, but has not been removed surgically.
• Group IV = Distant metastatic disease present

The staging uses the classic TNM system, defined as follows:

• T1 - Confined to site of origin
  • a < 5 cm
  • b > 5 cm
• T2 - Extension beyond site of origin
  • a < 5 cm
  • b > 5 cm
• N0 – no clinically involved lymph nodes
• N1 – clinically involved lymph nodes
• M0 – no distant disease
• M1 – distant disease
  • Stage I = Favorable sites, any size, any nodal status
  • Stage II = Unfavorable sites, but small AND negative lymph nodes
  • Stage III = Unfavorable sites, small or large, BUT positive lymph nodes
  • Stage IV = Distant metastatic disease, regardless of site, size, or nodes
• After a patient is assigned group and stage, he or she may also be classified as "ow," "intermediate," or "high" risk. For the most part, stage I patients are low risk, stage II and III are intermediate risk, and stage IV are high risk.

How are rhabdomyosarcomas treated?

Treatment of these tumors truly requires a multidisciplinary approach, with important contributions from all 3 major fields of cancer therapy: surgery, chemotherapy, and radiation therapy. However, general clinical guidelines that apply to the majority of cases are very difficult to make because rhabdomyosarcomas behave extremely differently, depending on the type and location of involvement.

Chemotherapy has been studied extensively in rhabdomyosarcoma patients. Some of the most active and studied chemotherapy drugs include: vincristine (V); actinomycin D (A); cyclophosphamide (C); and doxorubicin (Adr). We know that, even when a rhabdomyosarcoma is completely removed, the child remains at high risk for development of metastatic disease. For this reason, chemotherapy is used for all patients to treat any microscopic cells that may be present in lymph nodes or the bloodstream. With use of aggressive chemotherapy, the risk of metastatic disease is reduced dramatically.

In addition to chemotherapy, patients require surgery, radiation, or a combination of these two for a phase of treatment called "ocal control." Although all rhabdomyosarcomas are biopsied surgically at the time of diagnosis, some are then completely removed surgically. Others are mostly or partly removed. Still others can't be removed safely. If the tumor can be removed completely, often only surgery and chemotherapy are employed. If the surgeon or pathologist are concerned that microscopic cells may have been left behind after surgery, either at the tumor margin or in the lymph nodes, post-operative radiation will likely be recommended. If the tumor cannot be removed at all, higher-dose radiation is utilized.

Delivery of radiation may be done with x-rays, often using a technique called intensity modulated radiation treatment (IMRT), or with proton therapy. Proton therapy is available at some specialized centers around the world, and may offer advantages during treatment of rhabdomyosarcomas through reduction of radiation to normal, growing tissues.

Finally, here are some general facts and treatment guidelines on specific disease sites.

Bladder

• Usually develops as a pedunculated mass which may extend laterally and, in boys, deeply into the prostate, making origin difficult to determine
• Accounts for 50% of pelvic rhabdomyosarcomas
• Dysuria, polyuria, and urinary retention are early signs
• Ultrasound and cystoscopy are used to diagnose
• 90% are embryonal, including botryoid ("cluster of grapes") subtype
• Induction chemo followed by limited resection if bladder preservation is possible
• Alternatively, induction chemo followed by RT, then biopsy to document pathologic complete response (pCR = no more microscopic tumor seen). If no pCR, then limited surgery
• 4-yr overall survival = 90%, with bladder preservation rate of 60%

Prostate

• Tend to disseminate early and be more locally invasive
• Similar presentation to that of bladder
• Local measures should be pursued aggressively upfront

Paratesticular

• Painless unilateral scrotal swelling
• Frequently spreads through lymphatics to para-aortic lymph nodes
• Retroperitoneal lymph node dissection is common
• 5-yr overall survival > 80%

Vagina and Vulva

• Very young children
• Usually botryoid subtype of embryonal
• Treatment requires anterior exenteration with urinary diversion and chemotherapy
• 5-yr overall survival 60-80%

Uterus and Cervix

• Bleeding is common presentation
• Presents around puberty
• Polypectomy then chemo is highly curative

Extremity

• Relatively poor prognosis
  • high incidence of alveolar subtype
  • often locally lymph node positive
  • often metastatic at presentation
• Regional lymph node involvement may occur ~15%
• Chemo for all
• RT unless small, node negative, and completely excised

Parameningeal

• Embryonal > alveolar (4:1)
• Successful surgery is nearly always impossible, so surgery is typically for diagnosis only (biopsy)
• Neck dissection is morbid and not warranted
• RT delivered at beginning of treatment course if clear meningeal involvement or intra cranial extension
• Otherwise, chemo first, with RT following. Proton therapy may offer significant advantage for these patients through sparing of normal tissues, including the brain.

Orbit

• Often diagnosed early
• Eye swelling and displacement
• RT is the local modality of choice. Proton therapy may offer significant advantage for these patients through sparing of normal tissues, including the brain and the healthy eye.

Trunk

• Chest wall and paraspinal area
• Treat with as wide an excision as safely possible
• Then follow with chemotherapy and radiation
• Proton therapy may offer significant advantage for these patients through sparing of normal tissues.

Retroperitoneal

• Usually large and difficult to resect
• Lymph node involvement is common
• Prognosis is usually worse than for any other type
• Radiation is often needed, and proton therapy may offer significant advantage for these patients through sparing of normal tissues.

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