Rhabdomyosarcoma (RMS) (from Greek, rhabdo, meaning rod shape, and myo, meaning muscle) is the most common soft tissue sarcoma in children. Although Weber first described RMS in 1854, a clear histologic definition was not available until 1946, when Stout recognized the distinct morphology of rhabdomyoblasts. Stout described rhabdomyoblasts as appearing in round, strap, racquet, and spider forms. As its name suggests, the tumor is believed to arise from a primitive muscle cells. Rhabdomyoblasts sometimes have discernible muscle striations that are visible on specimens under light microscopy, though electron microscopy may be needed to detect subcellular elements. Cells are usually positive for intermediate filaments and other proteins typical of differentiated muscle cells, such as desmin, vimentin, myoglobin, actin, and transcription factor myoD.

Several distinct histologic groups have prognostic significance, including embryonal RMS (ERMS, which occurs in 55% of patients), the botryoid variant of ERMS (5% of patients), alveolar RMS (ARMS, 20% of patients), and undifferentiated sarcoma (UDS, 20% of patients).

Treatment responses and prognoses vary widely depending on location and histology. Studies tumor biology and treatment in patients with RMS at a single institution, or even at regional centers, are not possible because of the variable nature and uncommon occurrence of the tumors. Therefore, most advances in knowledge and treatment have resulted from cooperative group studies.

Pathophysiology

Although the tumor is believed to arise from primitive muscle cells, tumors can occur anywhere in the body except bone. The most common sites are the head and neck (28%), extremities (24%), and genitourinary (GU) tract (18%). Other notable sites include the trunk (11%), orbit (7%), and retroperitoneum (6%). RMS occurs at other sites in <3% of patients. The botryoid variant of ERMS arises in mucosal cavities, such as the bladder, vagina, nasopharynx, and middle ear. Lesions in the extremities are most likely to have an alveolar type of histology. Metastases are found predominantly in the lungs, bone marrow, bones, lymph nodes, breasts, and brain.

As with most tumors of childhood, the cause of RMS is unknown. The alveolar variant is so named because of the thin criss-crossing fibrous bands that appear as spaces between cellular regions of the tumor (reminiscent of lung alveoli). This variant is usually associated with 1 of 2 chromosomal translocations, namely, t(2;13) or t(1;13). These result in the fusion of the DNA-binding domain of the neuromuscular developmental transcription factors, encoded by PAX3 on chromosome 2 or PAX7 on chromosome 1. The transcriptional activation domain of a relatively ubiquitous transcription factor, FKHR (or FOXO1a) is encoded on chromosome 13.

The resulting hybrid molecule is a potent transcription activator. It is believed to contribute to the cancerous phenotype by abnormally activating or repressing other genes. The embryonal subtype usually has a loss of heterozygosity at band 11p15.5; this observation suggests the presence of a tumor suppressor gene. Other molecular aberrations that may provide clues to the origin of the tumor and that may be useful for future treatment strategies include TP53 mutations (which occurs in approximately one half of patients), an elevated N-myc level (in 10% of patients with ARMS), and point mutations in N-ras and K-ras oncogenes (usually embryonal). In addition, levels of insulinlike growth factor-2 may be elevated, suggesting pathways involving autocrine and paracrine growth factors.

Frequency

United States

The incidence is 6 cases per 1,000,000 population per year (approximately 250 cases) in children and adolescents younger than 15 years.

International

No notable geographic predilection is reported.

Mortality/Morbidity

In patients with localized disease, overall 5-year survival rates have improved to >80% with the combined use of surgery, radiation therapy, and chemotherapy. However, in patients with metastatic disease, little progress has been made in survival rates, with a 5-year event-free survival rate <30%. The use of high-dose myeloablative therapy with autologous stem-cell rescue has not improved outcomes for these patients.

In a recent analysis of data collected by the Surveillance, Epidemiology, and End Results (SEER) program, mortality was highly related to age, site, and histology. The 5-year survival was highest for children aged 1-4 years (77%) and worst for infants and adolescents (47% and 48%, respectively). Orbital and GU sites were the most favorable (86% and 80%, respectively). Unfavorable sites included tumors of the extremities (50%), retroperitoneum (52%), and trunk (52%). Embryonal histology was best (67%) compared with alveolar histology (49%).

Race

No racial predilection is obvious.

Sex

Overall, the male-to-female ratio is 1.2-1.4:1. Differences exist according to the site of primary disease.

—      GU tract: The male-to-female ratio is 3.3:1 in patients with bladder or prostate involvement and 2.1:1 in RMS of the GU tract without bladder or prostate involvement.

—      Extremity: The male-to-female ratio is 0.79:1.

—      Orbit: The male-to-female ratio is 0.88:1.

Age

Approximately 87% of patients are younger than 15 years, and 13% of patients are aged 15-21 years. RMS rarely affects adults. Age-related differences are observed for the different sites of primary disease. Two age peaks tend to be associated with different locations. Patients ages 2-6 years tend to have head and neck or GU tract primary tumors, whereas adolescents aged 14-18 y tend to have primary tumors in extremity, truncal, or paratesticular locations.

—      GU tract: In patients with bladder or prostate involvement, 73% are younger than 5 years. In patients with RMS of the GU tract without bladder or prostate involvement, 27% are older than 15 years.

—      Orbit: About 42% of patients with orbital RMS are aged 5-9 years.

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