Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a malignant soft tissue tumour whose cells are committed to skeletal-muscle differentiation. It is the most common soft tissue sarcoma of childhood and one of the more frequent solid tumours in children overall.

A muscle cancer wherever it arises. RMS does not need pre-existing skeletal muscle to form. It arises from primitive mesenchymal cells that activate the skeletal-muscle differentiation programme (MyoD1, myogenin), which is why it can arise anywhere, including sites that contain no striated muscle, such as the bladder, biliary tree and orbit.

Who. Most cases are under 10 years, with a smaller second peak in adolescence and a slight male predominance overall. The biology is bimodal as well: embryonal tumours dominate in young children, alveolar tumours in older children and teens. Adults are rarely affected and have a substantially poorer prognosis, partly because of more frequent pleomorphic histology, unfavourable sites and later presentation.

Where. Head and neck is the most common region, and extremity disease is the form most relevant to orthopaedic practice.

• Head and neck, including the orbit and parameningeal sites
• Genitourinary: bladder, prostate, paratesticular, vagina
• Extremity: more often alveolar, with a higher rate of nodal involvement
• Trunk, retroperitoneum and other sites

Site carries prognosis. Parameningeal and extremity sites carry the worst outlook, as does any metastatic disease. The parameningeal primaries are the nasopharynx, paranasal sinuses, middle ear and infratemporal fossa, and they carry a worse prognosis because of their proximity to the skull base.

The myogenic programme. RMS cells express the master regulators of skeletal-muscle differentiation, MyoD1 and myogenin (MYF4), together with structural muscle proteins such as desmin. This myogenic signature is the basis for diagnosis on immunohistochemistry.

Fusion-positive RMS. These tumours are defined by gene fusions involving FOXO1, which drive an aggressive transcriptional programme. Most morphologically alveolar tumours are fusion-positive.

• PAX3-FOXO1, t(2;13): the most common, with the worst prognosis
• PAX7-FOXO1, t(1;13): less common, with somewhat better behaviour

Fusion-negative RMS. There is no FOXO1 fusion, and the tumour is driven by other mutations, of which RAS pathway mutations are common. The group includes most embryonal tumours and generally has a better prognosis than fusion-positive disease.

Other recurrent drivers. These alterations recur alongside, or instead of, the fusion.

The WHO recognises embryonal, alveolar, pleomorphic and spindle cell/sclerosing subtypes.

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Embryonal (ERMS). The most common subtype, typically in younger children and at head and neck and genitourinary sites. It is usually FOXO1 fusion-negative, with frequent RAS pathway mutations, and generally has a favourable prognosis.

• Primitive small round to spindle cells in a myxoid stroma
• Variable rhabdomyoblasts with eosinophilic cytoplasm (tadpole or strap cells)
• Alternating cellular and loose hypocellular areas
• Botryoid variant: grape-like polypoid growth under mucosa (bladder, vagina), with a cambium layer

The botryoid variant is favourable. Spindle-cell morphology is not reliably so: see spindle cell/sclerosing RMS below.

Alveolar (ARMS). More common in older children and adolescents, often at extremity and trunk sites, with frequent nodal involvement. Most are PAX3-FOXO1 or PAX7-FOXO1 fusion-positive, and that is why the subtype has a worse prognosis than embryonal disease.

• Small round cells in nests separated by fibrovascular septa
• Discohesive cells creating the "alveolar" spaces
• A solid variant lacks well-formed alveolar spaces

Every morphologically alveolar tumour must undergo FOXO1 fusion testing. A fusion-negative result reclassifies the patient into the lower-risk, embryonal-like category and can change treatment intensity, so never assign risk on morphology alone; wait for the fusion result.

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Pleomorphic RMS. Almost exclusively a tumour of adults, in deep extremity soft tissue. It is made of bizarre pleomorphic cells with no FOXO1 fusion, and it is aggressive, often chemoresistant and carries a poor prognosis.

Spindle cell / sclerosing RMS. A sclerosing pattern with dense hyalinised stroma, easily mistaken for other spindle cell tumours. The congenital/infantile form (VGLL2/NCOA2) is favourable; the adult MYOD1-mutant form is highly aggressive.

Immunohistochemistry. The diagnosis rests on the nuclear myogenic transcription factors, myogenin and MyoD1, supported by desmin; fusion testing then sets the risk.

The myogenin pattern is a clue. Diffuse, strong nuclear myogenin is typical of alveolar (often fusion-positive) tumours, whereas embryonal tumours tend to show more patchy staining. Combine immunohistochemistry with molecular fusion testing for definitive classification.

Morphology varies. RMS is a small round blue cell tumour of skeletal-muscle lineage, but an epithelioid variant forms organoid nests rather than the classic spindled or alveolar patterns. Morphology alone is unreliable, which is why immunohistochemistry is mandatory. Beware cross-reactivity as well: this epithelioid variant also expressed TTF-1, a marker normally taken to indicate lung or thyroid origin, and a panel rather than a single stain is what avoids the trap.

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History. A painless or painful enlarging mass at the primary site, and rapid growth is common. Constitutional symptoms suggest metastatic disease. The rest depends on where the tumour sits:

• Orbit: proptosis
• Parameningeal: nasal obstruction or cranial nerve palsy
• Bladder: haematuria or urinary obstruction
• Paratesticular: a painless scrotal mass

Red flags. Look specifically for:

• Cranial nerve palsy or meningeal symptoms, pointing to parameningeal extension
• A deep, firm, enlarging extremity mass in a child or adolescent
• Regional lymphadenopathy, especially with extremity and paratesticular tumours
• Bone pain or pancytopenia, pointing to marrow involvement

Examination. Inspect the size and site of the mass, the skin and overlying vascularity, any proptosis or facial asymmetry, and functional impairment of the adjacent joint or organ. Palpate for consistency, fixity and relation to deep structures, for tenderness and the neurovascular relationship, and assess the regional lymph nodes, which is important for extremity and paratesticular tumours.

Regional and systemic examination. Examine the cranial nerves for head and neck tumours and the distal neurovascular status for extremity tumours. Finish with a general examination for hepatosplenomegaly, bone tenderness and signs of marrow failure.

The modalities. Each has a defined role:

• Chemotherapy: vincristine, actinomycin D (dactinomycin) and cyclophosphamide (VAC) form the backbone; ifosfamide-containing and other regimens are used in different cooperative groups, with intensification for higher risk
• Surgery: complete resection where it can be achieved without unacceptable morbidity; otherwise biopsy followed by chemotherapy and delayed local control
• Radiotherapy: for microscopic or gross residual disease, nodal involvement and most alveolar tumours; its near-universal role is set out below

De-escalation in the lowest-risk patients. Cooperative-group trials have shown that the lowest-risk embryonal patients can be treated with shorter therapy and reduced or omitted cyclophosphamide while maintaining excellent failure-free survival. That reduces long-term toxicity such as infertility and second malignancy, and it is a key example of evidence-driven de-escalation.

Radiotherapy is near-universal. A defining feature of RMS, set against adult soft-tissue sarcoma, is how central radiotherapy is to local control. Because chemotherapy is universal and complete excision is often unachievable without mutilation, almost every RMS patient receives radiotherapy; the principal exception is the patient with completely resected, group I embryonal disease at a favourable site, who may avoid it. Microscopic residual (group II), gross residual (group III), nodal disease and essentially all alveolar/fusion-positive tumours get radiotherapy.

How it is delivered in a growing child. The late effects (growth arrest, asymmetry, organ damage, second malignancy) are lifelong, so the priority is function- and growth-sparing planning rather than dose escalation.

• Proton beam therapy is increasingly used to reduce dose to adjacent growing bone, brain (parameningeal and orbital tumours) and viscera
• Brachytherapy, for example for selected genitourinary/vaginal and small extremity tumours, delivers a high local dose over a small volume, sparing surrounding growth plates and organs

The surgeon's role. In adult extremity soft tissue sarcoma surgery is often the primary treatment. In rhabdomyosarcoma chemotherapy is universal and surgery is integrated into a multimodal plan, in a decision sequence:

1. Upfront resection, when feasible. Considered when complete excision with negative margins is achievable without major functional loss or mutilation, which suits small, favourable, resectable tumours (paratesticular, some extremity lesions). It avoids or reduces radiotherapy in selected patients.
2. Biopsy then chemotherapy, in most cases. Larger or unfavourable-site tumours have a diagnostic biopsy only, then neoadjuvant chemotherapy to shrink the tumour, and are reassessed for delayed primary resection or definitive radiotherapy.
3. Delayed local control, after response. Delayed primary excision can convert a group III tumour to a resected state. Radiotherapy is used when surgery would be mutilating or margins remain positive, and function preservation is prioritised, especially in children.

Extremity tumours. Limb salvage with wide margins is the goal. Amputation is rarely needed and is reserved for tumours not controllable by surgery plus radiotherapy, and reconstruction and rehabilitation planning are essential in growing children.

Do not forget the nodes. Extremity and paratesticular rhabdomyosarcomas have a high rate of regional nodal spread, so formal nodal assessment is part of their staging and clinical and radiological evaluation is mandatory. Imaging alone understages the nodes, and these primaries warrant surgical nodal staging: sentinel or regional node sampling guides radiotherapy fields and systemic intensity, and missed nodal disease leads to undertreatment and predicts relapse.

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The price of local control. Growth impairment, limb length discrepancy and second malignancy are the price of irradiating a growing child, and must be discussed before treatment.

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Outcome by risk. The spread is wide, from high cure rates to poor survival, and it follows the risk group.

• Low-risk localised disease (favourable site, embryonal/fusion-negative): high cure rates with risk-adapted therapy
• Intermediate-risk disease: intermediate survival; benefits from full multimodal therapy
• Metastatic or high-risk disease: poor survival despite intensified treatment
• Adult and pleomorphic RMS: markedly worse than paediatric disease

Prognostic factors. The same factors feed risk grouping and prognosis.

Integrating molecular risk. The shift from histology-based to fusion-based risk stratification, supported by international genomic data, is refining who needs intensification and who can be de-escalated. Incorporating additional drivers (e.g. MYOD1, TP53) into routine risk grouping is an active area of trial design.

De-escalation against cure. Reducing cyclophosphamide and shortening therapy in low-risk patients lowers late toxicity. The balance between minimising harm and maintaining cure rates must be confirmed in each subgroup before it is adopted as standard.

Adult rhabdomyosarcoma. Adults are frequently treated on paediatric-style protocols, and those who receive intensive multimodal therapy fare better than historical adult cohorts, yet outcomes remain inferior to children. Optimal regimens for adults are still debated.

Relapsed and metastatic disease. Outcomes after relapse, and for metastatic disease at presentation, remain poor. New agents (targeted therapy against the RAS pathway, immunotherapy and antibody-based approaches) are under investigation, and trial enrolment is encouraged.

Global Epidemiology

Cooperative-Group Frameworks

High- vs Limited-Resource Practice Variation