Rhabdomyosarcoma

Basics

Description

A soft tissue cancer with features of skeletal muscle differentiation. Prognostic classification of rhabdomyosarcoma (RMS) currently depends on:

  • Anatomic site of disease (stage)
  • Extent of resection and spread (group)
  • Presence of a FOXO1 gene fusion (either PAX3-FOXO1 or PAX7-FOXO1). This has supplanted histologic subtype (alveolar vs. embryonal) in North America.

Epidemiology

  • The most common pediatric soft tissue sarcomas (tumors of mesenchymal origin)
  • Accounts for ~5% of childhood cancer
  • Boys at slightly increased risk compared to girls (incidence by gender of 1.5:1)

Incidence

  • 4.5 cases per 1 million children per year
  • U.S. annual incidence is approximately 350 cases per year.
  • Age distribution
    • Peaks in children <7 years, with another smaller peak in late adolescence
    • Median age at diagnosis is 5 years.

Risk Factors

Genetics

  • About 90% of cases are sporadic.
  • Several predisposing conditions:
    • Li-Fraumeni (autosomal dominant)
      • TP53 mutation leads to cancer predisposition due to inadequate response to DNA damage.
      • Increased risk for soft tissue sarcomas, osteosarcoma, adrenocortical carcinoma, choroid plexus carcinoma, leukemias, breast cancer, and other cancers
    • Beckwith-Wiedemann syndrome (sporadic)
      • Improper epigenetic regulation of 11p15 leads to an overgrowth syndrome.
      • Increased risk of a range of embryonal cancers early in life, including Wilms tumor, hepatoblastoma, and RMS
    • Neurofibromatosis type I and Costello syndrome (autosomal dominant)
      • Mutational activation of HRAS (Costello) or loss of the RAS-negative regulator NF1 (neurofibromatosis) leads to unchecked RAS signaling and increased risk for RMS.

General Prevention

  • No standard approach because usually sporadic
  • Avoidance of radiation in patients with known predisposing syndromes (e.g., Li-Fraumeni syndrome)

Pathophysiology

  • Chromsomal translocations (most commonly t[2;13] or t[1;13]) create fusion transcription factors PAX3-FOXO1 and PAX7-FOXO1.
    • Fusions are usually found in alveolar histology tumors, but fusion-negative alveolar cases have a superior prognosis.
    • Animal models combining expression of PAX3-FOXO1 and loss of either TP53 or CDKN2A recapitulate RMS.
  • Fusion-negative RMS (~60% of cases) commonly carry mutations in the RAS pathway, as well as loss of heterozygosity at 11p15.
    • Animal models of fusion-negative RMS target activating RAS mutations to myogenic progenitor cells.
  • Distinct histologies include pleomorphic or anaplastic RMS, which harbor poor prognoses.

Commonly Associated Conditions

  • Syndromes listed in “Genetics” section have the highest association.
  • Radiation exposure, including a possible connection to in utero exposure.
  • Single studies showed an association with high birth weight or incomplete childhood vaccination, respectively.

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