Description

• Rhabdomyosarcoma (RMS) is a malignant soft tissue tumor presumed to originate from a mesenchymal cell line shared with striated skeletal muscle.
• Occurs mainly as primary malignancy but can also be a component of heterogeneous neoplasms
  • WHO classification of soft tissue tumors describes four main RMS subtypes:
    • Embryonal RMS (ERMS): 60% of RMS cases
      • Early onset and the most common subtype in children
      • Commonly presents in the head, neck, and genitourinary areas
      • Subdivided into:
        • Classic
        • Botryoid (6% overall embryonal): seen in infants, although can happen in <4-year-old patients
        • Spindle cell: 3% of cases and affects young children
        • Both botryoid and spindle cell variants have better prognosis than the classic variant
    • Alveolar RMS (ARMS): 20% of pediatric cases
      • Aggressive subtype
      • More common in the trunk, perineum/perianal area, and extremities
    • Spindle/Sclerosing: approximately 10% of cases
      • Mostly found in the paratesticular region
    • Anaplastic (children)/pleomorphic (adults): <10% of cases
      • Typically seen in patients aged 30 to 50 years (rarely in pediatric population)
      • Associated with Li-Fraumeni symptoms
      • Demonstrates hyperchromatic enlarged nuclei
  • Pathologic and molecular studies have now delineated up to five or six distinct subfamilies of RMS.
  • Common primary sites:
    • Head and neck (25%) presentation (common in young children, usually embryonal type)
    • Genitourinary (31%, mostly embryonal type)
    • Musculoskeletal (13%, most common in extremities primary sites in adolescents and adults, alveolar subtype)

Epidemiology

• RMS is the most common soft tissue sarcoma in pediatric population.
• Common metastatic sites: bone marrow, lung, lymph nodes

Incidence

• 4.5 cases of RMS per 1 million children per year
• Accounts for 50% of all soft tissue sarcomas in children and adolescents
  • 50% of pediatric cases occur before the age of 10 years (often before age 6 years).

Prevalence

• Represents 3% of all pediatric tumors and 1% of all adult tumors
• Slight predilection for males (1.3:1 male-to-female ratio)
• More common in the African-American population

Etiology and Pathophysiology

• Originates from rhabdomyoblast cell
• Tumor is often >5 cm in size with poorly circumscribed border, white coloration, and infiltrative features.

Genetics
Genetic characteristics vary according to the RMS subtype:

• Alveolar:
  • Linked to recurrent Forkhead box O1 (FOXO1) fusions (identified in 90% of cases)
  • t(1;13)(p36;q14), causing formation of the fusion oncogenes PAX7-FOXO1
  • t(2;13)(q35;q14), causing formation of the fusion oncogenes PAX3-FOXO1
• Embryonal:
  • Multiple complex genetic aberrations, including MYOD1 mutations
  • Loss or uniparental disomy of 11p15.5 +2, +8, +11, +12, +13, +20 affecting genes IGF-2, H19, CDKN1C, and/or HOTS
• Spindle cell/sclerosing:
  • 8q13 rearrangements involving SRF-NCOA2 and TEAD1-NCOA2

Risk Factors

Largely unknown; however, appears to be increased risk of RMS in setting of:

• Rapid growth in utero
• Radiation exposure in utero
• Lower socioeconomic status
• Recreational drug use during pregnancy

Commonly Associated Conditions

• Beckwith-Wiedemann syndrome (11p15 mutations)
• Costello syndrome (germline HRAS mutations)
• Li-Fraumeni syndrome (germline TP53; known as p53 mutations)
• Neurofibromatosis type I (NF1 mutations)
• Noonan syndrome (PTPN11 mutations)