Rhabdomyosarcoma

Rhabdomyosarcoma is a malignant mesenchymal neoplasm believed to originate from cells with characteristics of skeletal muscle. The World Health Organization recognizes four subtypes: alveolar, embryonal, spindle cell/sclerosing, and pleomorphic. Rhabdomyosarcoma is also one of the five soft-tissue sarcomas with a known propensity for lymph node metastasis. These five, represented by the “SCARE” acronym, include Synovial sarcoma, Clear cell sarcoma, Angiosarcoma, Rhabdomyosarcoma, and Epithelioid sarcoma.

Epidemiology

In the United States, approximately 500 cases of rhabdomyosarcoma are diagnosed each year. It is the most common soft-tissue sarcoma in children and adolescents, accounting for 3% of all pediatric tumors and about half of all pediatric soft-tissue sarcomas. Among adults, rhabdomyosarcoma is much rarer, comprising only about 1% of 1% of soft tissue sarcomas. The overall incidence is approximately 4.4 cases per million individuals aged 0-20 years, with half of these cases occurring in children under 10 years of age. There is a slight male predominance, with a male-to-female ratio of 1.3:1, and about 80% of cases occur in Caucasians.

The most common subtype, embryonal rhabdomyosarcoma, affects approximately 2.6 per million children under age 15. A distinct dubtype of Embryonal Rhabdomyosarcoma is Botryoid Rhabdomyosarcoma. This name comes from the Greek word for “bunch of grapes” because these tumors present as a grape-like polypoid mass. These are most common in inta-abdominal locations and have a more favorable prognosis. Alveolar rhabdomyosarcoma, the second most common subtype, occurs at a rate of about 1 per million children and adolescents. Alveolar and pleomorphic rhabdomyosarcomas tend to present in older children and adolescents, while embryonal rhabdomyosarcoma is predominantly diagnosed in younger children. Rare variants within the spindle cell/sclerosing and pleomorphic categories collectively account for about 2% of pediatric rhabdomyosarcoma cases.

Clinical Features

Rhabdomyosarcoma typically presents as a growing, deep-seated soft-tissue mass that is often painless. Embryonal rhabdomyosarcoma tends to present as localized disease in about 75% of cases, compared to about 60% for alveolar and 50% for pleomorphic rhabdomyosarcoma.

Rhabdomyosarcoma can occur throughout the body, with specific subtype associations by location. Head, neck, and genitourinary tumors are more frequently embryonal rhabdomyosarcomas, whereas extremity tumors are more commonly alveolar. Younger children (under 6 years old) are more likely to present with head, neck, or genitourinary tumors, while teenagers tend to have para-testicular, trunk, abdominal, or extremity tumors.

Radiologic Features

All patients with suspected rhabdomyosarcoma should undergo thorough imaging for both local disease assessment and metastasis evaluation. Local site imaging includes magnetic resonance imaging (MRI) with and without contrast. A chest CT is essential to evaluate potential pulmonary metastases. Whole-body imaging is recommended to assess marrow and lymph node involvement, using either fluorodeoxyglucose (FDG) positron emission tomography (PET-CT) or a whole-body bone scan.

MRI is generally preferred over CT for evaluating extremity soft-tissue tumors. On MRI, rhabdomyosarcoma typically appears isointense to muscle on T1-weighted images, with intermediate to high signal intensity on T2-weighted images and shows significant enhancement following contrast administration (Figure 1). Most rhabdomyosarcoma masses display internal heterogeneity, with alveolar rhabdomyosarcoma often exhibiting a more lobulated appearance on MRI.

Figure 1: (A) T1 axial, (B) T2 fat-suppressed sagittal, and (C) T1 fat-suppressed post-contrast axial MRI sequences of pleomorphic rhabdomyosarcoma of the right hip/buttock. Note the hypointensity on T1, heterogeneous hyperintensity on T2, and heterogeneous internal contrast enhancement on post-contrast sequences.

Pathology

Rhabdomyosarcoma is generally classified as a small round blue cell tumor, a category that includes other malignancies with similar histologic features, such as Ewing sarcoma and neuroblastoma. Histologic features vary by subtype, but all subtypes are immunohistochemically positive for skeletal muscle markers, including desmin, myogenin, and MyoD1.

Embryonal rhabdomyosarcoma resembles embryonic skeletal muscle, with small round cells and skeletal muscle tissue in various stages of development. Cross-sectional striations are visible in approximately 50% of cases (Figure 2).

Figure 2: (A) H&E stain, embryonal rhabdomyosarcoma: Patternless sheets of spindled, stellate, and ovoid cells with hyperchromatic nuclei and amphophilic cytoplasm. Mitoses are common (arrows). (B) MyoD1 stain, embryonal rhabdomyosarcoma: Diffuse nuclear MyoD1 staining. (Image courtesy of Drs. Andrew Horvai and Amir Qorbani.)

Alveolar rhabdomyosarcoma presents as a highly cellular, monomorphous population of primitive cells with round nuclei, demonstrating features of arrested myogenesis. Most cases exhibit PAX3-FOXO1 (t(2;13)) or PAX7-FOXO1 (t(1;13)) fusion genes.

Spindle Cell/Sclerosing rhabdomyosarcomas are characterized microscopically by a fascicular or storiform growth pattern, composed of spindle-shaped neoplastic cells with ovoid or elongated nuclei. Nuclear atypia, hyperchromasia, and frequent mitotic figures are common.

Pleomorphic rhabdomyosarcoma consists of sheets of large, atypical round and spindle cells showing skeletal muscle differentiation without embryonal or alveolar components.

Differential Diagnosis

The differential diagnosis for small round blue cell tumors of soft tissue includes several malignancies, which can be remembered by the mnemonic MR SLEEP:

  • Melanoma (rare, but may present as a small round cell tumor)
  • Rhabdomyosarcoma
  • Sarcoma (specifically alveolar soft part sarcoma in this context)
  • Lymphoma
  • Ewing sarcoma/Primitive neuroectodermal tumor
  • Epithelioid sarcoma
  • Poorly differentiated carcinoma.

Disease Course: Treatment and Prognosis

In suspected cases of rhabdomyosarcoma, biopsy is essential for confirming the diagnosis, determining the specific subtype, and guiding treatment decisions. For extremity rhabdomyosarcoma, a sentinel lymph node biopsy at the time of diagnosis is recommended to assess lymph node involvement. Additionally, bone marrow aspirates or biopsies provide important information about the extent of disease and potential marrow involvement.

Rhabdomyosarcoma is generally treated aggressively with multimodal therapy, including neoadjuvant multiagent chemotherapy, surgery, radiation therapy, and adjuvant chemotherapy.

Survival is correlated with stage at presentation. Older age at diagnosis and the presence of metastatic disease are associated with a poorer prognosis. Embryonal rhabdomyosarcoma, which frequently presents with localized disease, has a relatively favorable prognosis, with an approximate 65% 10-year survival rate. Other subtypes, which more often present with metastatic disease, have lower 10-year survival rates, ranging from about 20% for pleomorphic tumors to around 50% for spindle cell tumors. Alveolar rhabdomyosarcoma has a 10-year survival rate of approximately 35%, though patients with localized alveolar rhabdomyosarcoma who undergo negative-margin surgery with neoadjuvant and adjuvant chemotherapy may achieve better outcomes.

Risk stratification for rhabdomyosarcoma is based on pretreatment staging and factors such as the site of origin, tumor extent, size, and the presence or absence of regional lymph node involvement or metastases.

The IRS (Intergroup Rhabdomyosarcoma Study) Clinical Group Classification categorizes rhabdomyosarcoma cases based on the extent of disease after initial surgical resection:

  • Group I: Localized rhabdomyosarcoma that is completely removed by surgery, accounting for approximately 10-15% of cases.
  • Group II: Residual microscopic disease after surgical removal, with cancer cells present at the specimen edges; about 20% of patients fall into this group.
  • Group III: Tumors that could not be fully removed surgically but show no signs of distant spread; this group includes around 50% of cases.
  • Group IV: Evidence of distant metastasis at diagnosis, such as to the lungs, liver, bones, bone marrow, or distant muscles and lymph nodes; this group represents 15-20% of cases.
  • This standardized classification system is essential for determining the appropriate treatment approach and for prognostication in rhabdomyosarcoma patients.

Key Test Topics

  • A poorer prognosis is associated with cases demonstrating a FOXO1 fusion rearrangement which is due to a translocation, usually between chromosomes 1 or 2 and chromosome 13. The most common forms are PAX3-FOXO1 and PAX7-FOXO1.
  • Embryonal rhabdomyosarcoma occurs primarily in younger children, is more likely to present as localized disease, and has the best prognosis of all subtypes.
  • Pleomorphic rhabdomyosarcoma is more common in adults and has a poor prognosis.
  • Rhabdomyosarcoma stains for skeletal muscle markers desmin, myogenin, and MyoD1.
  • Sentinel lymph node biopsy is part of the staging workup for extremity rhabdomyosarcoma.
  • Rhabdomyosarcoma is part of the “SCARE” mnemonic representing one of the sarcomas that can metastasize to lymph nodes.
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