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Rhabdomyosarcoma (RMS) in Children

Rhabdomyosarcoma is a malignant mesenchymal tumor with skeletal muscle differentiation and is the most common soft tissue sarcoma of childhood. It accounts for 3-4.5% of all pediatric malignancies, and in the head/neck region it is the dominant soft tissue sarcoma.

Subtypes

Four histologic subtypes are recognized. The first two are predominantly pediatric:
SubtypeFrequencyAgeKey Features
Embryonal~50%ChildrenSoft, gray, infiltrative; spindle/round cells in myxoid stroma; rhabdomyoblasts with strap-like cytoplasm and cross-striations
Alveolar~20%Children/adolescentsFirmer; round cells in alveolar pattern; PAX3/PAX7-FOXO1 fusions; worse prognosis
Pleomorphic~20%AdultsLarge multinucleate bizarre cells
Spindle cell/sclerosing~10%All agesFusiform cells in fascicles, storiform pattern
Sarcoma botryoides is a variant of embryonal RMS that grows as polypoid masses in hollow viscera (urinary bladder, vagina) - classically in young girls.

Histology

Fig. 19.44 (Robbins & Kumar Basic Pathology) - Rhabdomyosarcoma:
Rhabdomyosarcoma histology: (A) Embryonal type with primitive round to strap-shaped cells with cross-striations (arrows); (B) Alveolar type with dyscohesive round cells in alveolar spaces
(A) Embryonal subtype - malignant cells from primitive/round to eosinophilic with skeletal muscle differentiation (arrows). (B) Alveolar subtype - spaces lined by dyscohesive, uniform round tumor cells.
Fig. 204.3 (Cummings Otolaryngology) - Embryonal RMS:
Embryonal RMS: (A) stellate/spindle cells in myxoid background; (B) rhabdomyoblast with eccentric nucleus and eosinophilic cytoplasm (arrow) and mitotic figure (arrowhead)
(A) Stellate and spindle cells in a myxoid background. (B) Higher magnification showing a rhabdomyoblastic cell with eccentric nucleus and eosinophilic cytoplasm (arrow) and a mitotic figure (arrowhead).

Genetics / Molecular Biology

  • Alveolar RMS: Characterized by translocations t(2;13) or t(1;13), fusing PAX3 or PAX7 to FOXO1 (previously known as FKHR). PAX3 normally initiates skeletal muscle differentiation; the chimeric fusion protein interferes with differentiation and drives oncogenesis - a mechanism analogous to transcription factor fusions in acute leukemia. PAX3-FOXO1 fusions confer a worse prognosis.
  • Embryonal/Pleomorphic RMS: Genetically heterogeneous; no consistent single translocation.

Common Sites in Children

Pediatric RMS often arises in locations that do not normally contain much skeletal muscle, which supports origin from undifferentiated mesenchymal stem cells:
  1. Head and neck (~35%): Orbit (most common single subsite, ~25% of H&N RMS), parameningeal sites (middle ear/mastoid, nasal cavity, paranasal sinuses, parapharyngeal space, pterygopalatine/infratemporal fossa)
  2. Genitourinary tract: Bladder, prostate, vagina, paratesticular
  3. Extremities: Particularly alveolar subtype
Parameningeal tumors are close to the skull base and carry higher risk of intracranial extension.

Presentation

  • Firm, often asymptomatic mass (most common)
  • Site-specific symptoms: nasal obstruction, rhinorrhea, epistaxis, otitis media with aural polyp, proptosis (orbital), hematuria/urinary obstruction (GU), cranial nerve deficits (parameningeal)
  • Cranial nerve deficits suggest skull base erosion

Diagnosis and Workup

  • Biopsy (open or core): The definitive step
  • IHC: Muscle-specific proteins - myogenin (most specific), MyoD1, desmin, muscle-specific actin; cross-striations on H&E may be visible
  • Imaging:
    • MRI: Isointense to muscle on T1; high signal on T2; best for soft tissue extent and perineural spread
    • CT: Better for bony erosion (skull base assessment)
    • FDG-PET/CT: Sensitive for macroscopic metastatic disease
    • Technetium-99 bone scan: For osseous metastases
  • Staging workup: CBC, electrolytes, renal/liver function, coagulation; bone marrow aspirate and CSF cytology (for parameningeal/metastatic staging)

Staging

Two complementary systems are used together by the Children's Oncology Group (COG):

1. Pretreatment TNM Staging (Table 204.6)

StageSiteTumorSizeNodesMets
1Favorable (orbit, non-parameningeal H&N)T1 or T2AnyAny NM0
2UnfavorableT1 or T2≤5 cmN0/NXM0
3UnfavorableT1 or T2>5 cm or N1Any NM0
4AnyT1 or T2AnyAnyM1

2. COG Surgical-Pathologic Group (IRS Clinical Group)

GroupDefinition
ILocalized, completely resected, clear margins, no nodal disease
IICompletely removed but with microscopic residual OR involved regional nodes grossly removed
IIIIncomplete removal - gross residual disease after biopsy or subtotal resection
IVDistant metastases at diagnosis
These two systems, combined with histologic subtype, determine risk stratification (low, intermediate, high) which drives treatment intensity.

Treatment

Management is multimodal and guided by COG protocols. Pediatric patients should be enrolled in clinical trials when available.

Surgery

  • Complete surgical resection with clear margins is the goal when achievable without major functional morbidity
  • Mutilating operations are avoided - chemotherapy and radiation are given first to reduce tumor size (neoadjuvant approach) for unresectable disease
  • Accurate pathologic group assignment after surgery is critical

Chemotherapy

  • The backbone regimen is VAC (Vincristine, Actinomycin D, Cyclophosphamide) - established through decades of Intergroup Rhabdomyosarcoma Study Group (IRSG) trials
  • Higher-risk disease uses more intensive regimens

Radiation Therapy

  • Used for groups II-IV and selected group I alveolar tumors
  • Orbital RMS: Radiation as part of multimodal therapy (avoids enucleation)
  • Recent 2025 meta-analysis data (Fukushima et al., PMID 40494941) compared proton beam therapy vs. photon radiotherapy - proton therapy is increasingly preferred in children to spare surrounding tissues
  • For metastatic disease: Conditional recommendation for whole lung irradiation (WLI) at 15 Gy/10 fractions for pulmonary metastases (improves EFS but consistent OS benefit not proven); SABR 30-60 Gy/3-5 fractions for limited lung lesions

Prognosis

  • In the 1960s, 5-year OS was ~50%; with multimodal therapy it rose to ~70% by the 1990s and continues to improve
  • Favorable prognosis: Orbital location, embryonal histology, localized disease (Group I/II), Stage 1
  • Unfavorable prognosis: Alveolar histology (PAX3-FOXO1 especially), parameningeal location, metastatic disease (Group IV, Stage 4) - 5-year OS ~25% for metastatic disease
  • The botryoid variant of embryonal RMS carries a particularly good prognosis

Relapsed Disease

At least 1/3 of localized RMS and 60-70% of metastatic RMS experience progressive disease or relapse. The 2025 European pediatric soft tissue sarcoma study group (EpSSG) published treatment recommendations for relapsed RMS, and a 2026 systematic review (PMID 42093305) examines response outcomes as survival predictors in relapsed/refractory pediatric RMS.
Sources: Robbins & Kumar Basic Pathology, p. 802 | Cummings Otolaryngology Head and Neck Surgery, pp. 3853-3856 | Campbell's Operative Orthopaedics 15th Ed 2026, p. 1278 | Fukushima et al. 2025, Int J Clin Oncol, PMID 40494941 | Defachelles et al. 2025, Br J Cancer, PMID 40913059
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