Rhabdomyosarcoma

• Subtypes:
• Embryonal — the commonest, in younger children, favouring the head and neck (including orbit), and the genitourinary tract. The botryoid variant presents as a grape-like polypoid mass protruding from the vagina or bladder in an infant or young girl.
• Alveolar — adolescents, favouring extremities and trunk, with a worse prognosis and characteristic PAX3–FOXO1 or PAX7–FOXO1 fusions from t(2;13) or t(1;13).
• Pleomorphic — adults, rare.
• Presentation depends on site: a painless enlarging mass, proptosis with an orbital tumour, nasal obstruction or epistaxis, haematuria or urinary obstruction, or a vaginal mass.
• Histology and immunohistochemistry: rhabdomyoblasts with eosinophilic cytoplasm, sometimes with cross-striations; positive for desmin, myogenin and MyoD1.
• Treatment is multimodal — chemotherapy with surgery and/or radiotherapy — and outcomes depend on histology, site, and stage. Orbital and genitourinary primaries generally do better than parameningeal and extremity disease.

Non-modifiable — germline cancer predisposition (the syndromes examiners plant)

• **Li–Fraumeni syndrome (germline TP53)**: loss of the guardian of the genome permits accumulation of mutations in mesenchymal precursors; embryonal rhabdomyosarcoma in a toddler is one of the sentinel tumours, especially when a parent has early breast cancer or a sibling has adrenocortical carcinoma.
• DICER1 syndrome: defective microRNA processing; embryonal (botryoid) rhabdomyosarcoma of the cervix or uterus, often alongside pleuropulmonary blastoma, cystic nephroma or multinodular goitre.
• Neurofibromatosis type 1: loss of neurofibromin, a RAS-GAP, leaves RAS constitutively active — the same pathway mutated somatically in embryonal tumours.
• **RASopathies — Costello syndrome (germline HRAS) and Noonan syndrome**: Costello carries a particularly high embryonal rhabdomyosarcoma risk, prompting abdominal/pelvic ultrasound surveillance.
• Beckwith–Wiedemann syndrome: dysregulated imprinting at 11p15.5 with IGF2 overexpression — the same locus lost somatically in sporadic embryonal tumours (alongside Wilms tumour and hepatoblastoma).

Non-modifiable — somatic/demographic

• Fusion status: PAX3–FOXO1 t(2;13) or PAX7–FOXO1 t(1;13) defines fusion-positive (usually alveolar) disease; fusion-negative tumours carry *RAS*-pathway, FGFR4 and TP53 mutations. Fusion status, not histology alone, now drives risk assignment in Children's Oncology Group protocols.
• Age and sex: embryonal disease peaks in the first decade; alveolar disease is spread across adolescence and young adulthood. There is a slight male predominance.

Modifiable/environmental

• Essentially none is established. The overwhelming majority of cases are sporadic with no identifiable exposure. Associations proposed with parental smoking, recreational drug use, and in-utero radiographic exposure are inconsistent and are not the basis of any prevention recommendation; therapeutic ionising radiation is a recognised cause of second sarcomas generally.
• Practical implication: a child with rhabdomyosarcoma plus a suggestive family history or syndromic features warrants genetic counselling and germline testing, consistent with NCCN guidance on referral for suspected hereditary cancer syndromes.

• Cell of origin: a primitive mesenchymal cell committed to the myogenic program but arrested before terminal differentiation. Because the precursor — not mature muscle — is the origin, tumours arise where skeletal muscle is scarce or absent: orbit, bladder, prostate, vagina, biliary tree.
• Differentiation block: the cells transcribe the myogenic master regulators MyoD1 and myogenin and assemble intermediate filaments (desmin), yet cannot exit the cell cycle to fuse into myotubes. This is exactly why the immunohistochemical panel is positive while the histology shows sheets of small round blue cells with only occasional strap-shaped rhabdomyoblasts and cross-striations.

Fusion-positive (usually alveolar) biology

• PAX3–FOXO1 / PAX7–FOXO1 joins the PAX DNA-binding domain to the potent FOXO1 transactivation domain, creating a hyperactive transcription factor that establishes super-enhancers driving MYCN, MET, FGFR4 and IGF1R. The result is a genomically quiet but transcriptionally aggressive tumour — few mutations, high proliferative and metastatic drive, and diffuse strong myogenin staining.
• Clinically this translates into the alveolar phenotype: older children, extremity and trunk primaries, early regional nodal and marrow spread, worse survival.

Fusion-negative (usually embryonal) biology

• Loss of heterozygosity at 11p15.5 with loss of the maternal allele releases imprinted IGF2, producing autocrine growth stimulation; superimposed *RAS*-pathway, FGFR4 and TP53 mutations complete transformation. These tumours are aneuploid but clinically less aggressive.
• Botryoid growth occurs when an embryonal tumour expands in the submucosa of a hollow viscus (vagina, bladder, nasopharynx): unable to invade the epithelium, it condenses into a cambium layer of tumour cells beneath the mucosa and balloons into the lumen as translucent polypoid grape-like clusters.

• Symptom generation is therefore mass effect and local invasion — proptosis, obstruction, bleeding — followed by haematogenous dissemination to lung, bone and bone marrow and lymphatic spread in extremity and paratesticular primaries.

• The universal opening line: a painless, firm, enlarging mass in a child, without fever or weight loss. Systemic symptoms are late and usually signal marrow or bone metastases.

By primary site (the stem almost always names one)

• Orbit (embryonal, preschool child): rapidly progressive proptosis, globe displacement, ophthalmoplegia and diplopia from a retrobulbar mass. Vision is often preserved early; the orbit has essentially no lymphatic drainage, so nodal spread is rare.
• Parameningeal (nasopharynx, sinuses, middle ear, infratemporal fossa): nasal obstruction, epistaxis, chronic foul otorrhoea with an aural polyp, or sinusitis unresponsive to antibiotics. Cranial nerve palsies, headache or meningismus indicate skull-base erosion and intracranial extension — a high-risk feature.
• Bladder/prostate (embryonal, infant–toddler): haematuria, dysuria, urinary retention or a palpable suprapubic mass; obstruction may present as hydronephrosis or renal failure.
• Vagina/cervix: sarcoma botryoides — soft translucent grape-like polypoid tissue protruding from the introitus with blood-tinged discharge in an infant or young girl; cervical primaries in an adolescent should prompt thought of DICER1.
• Paratesticular (adolescent male): painless unilateral scrotal or inguinal swelling above the testis, with retroperitoneal nodal spread out of proportion to the small primary.
• Extremity/trunk (alveolar, adolescent): a firm deep mass, sometimes with regional lymphadenopathy — nodal involvement is far commoner here than in embryonal disease.
• Biliary tree: painless obstructive jaundice in a young child, mimicking a choledochal cyst.

Metastatic presentation

• Lung (usually asymptomatic, found on staging CT), bone (pain, pathologic fracture), bone marrow (pancytopenia, bone pain, a leukoerythroblastic smear that can be mistaken for leukaemia), and lymph nodes.
• Red-flag presentations demanding same-day action: airway compromise from a nasopharyngeal mass, spinal cord compression from paraspinal extension, and obstructive uropathy with rising creatinine.

Step 1 — imaging of the primary before any needle touches it

• MRI with contrast is the study of choice for soft-tissue extent, neurovascular involvement and, for parameningeal tumours, intracranial and skull-base extension; CT adds bony erosion detail. Image first so that biopsy artefact does not obscure tumour margins.

Step 2 — tissue (the confirmatory step)

• Core-needle or incisional biopsy planned with the surgeon who will perform definitive resection, placed so the tract can be excised and does not contaminate uninvolved compartments. Fine-needle aspiration is inadequate — molecular and immunohistochemical studies need architecture and volume.
• Histology: a small round blue cell tumour with rhabdomyoblasts showing dense eosinophilic cytoplasm and occasional cross-striations. Embryonal tumours are loosely cellular with a cambium layer beneath mucosa in botryoid lesions; alveolar tumours show nests of cells separated by fibrovascular septa with loss of central cohesion.
• Immunohistochemistry: desmin, myogenin and MyoD1 positive (nuclear myogenin staining is diffuse and strong in fusion-positive disease). This panel separates rhabdomyosarcoma from the other small round blue cell tumours — Ewing sarcoma (CD99, EWSR1–FLI1), lymphoblastic lymphoma (CD45/TdT), and neuroblastoma (synaptophysin, elevated urinary HVA/VMA).
• Molecular testing is mandatory: FISH or RT-PCR for FOXO1 rearrangement, since fusion status — not morphology alone — drives Children's Oncology Group risk assignment.

Step 3 — staging workup

• CT chest (lung is the commonest metastatic site), FDG-PET/CT (or bone scan) for osseous and nodal disease, bilateral bone marrow aspirate and biopsy, and lumbar puncture with CSF cytology for parameningeal primaries. Regional nodal sampling/sentinel node biopsy is recommended for extremity and paratesticular primaries.

Named systems

• Pretreatment TNM stage (favourable vs unfavourable site, tumour ≤5 cm vs >5 cm, nodes, metastases), the IRS Clinical Group I–IV assigned after initial surgery by residual disease, and COG risk group (low/intermediate/high) combining stage, group and fusion status.

Immediate stabilisation (before oncologic therapy)

• Secure the airway in nasopharyngeal obstruction, relieve obstructive uropathy (catheter or nephrostomy), and treat spinal cord compression with corticosteroids and urgent neurosurgical/radiation-oncology input. Correct tumour lysis risk with hydration before starting chemotherapy in bulky disease.

Systemic therapy — every patient receives chemotherapy, regardless of how completely the tumour was resected

• Alkylator/antimicrotubule/antitumour-antibiotic backbone: VAC — vincristine, dactinomycin and cyclophosphamide — is the standard regimen in Children's Oncology Group protocols; European (EpSSG) practice substitutes ifosfamide (IVA).
• Escalation for intermediate/high risk: addition of a topoisomerase I inhibitor, irinotecan (VAC alternating with vincristine/irinotecan), and in European protocols maintenance vinorelbine plus low-dose oral cyclophosphamide after induction in high-risk disease.
• Supportive care: mesna with cyclophosphamide/ifosfamide, growth-factor support, and Pneumocystis prophylaxis; febrile neutropenia is managed per IDSA guidance.

Local control — chemotherapy alone never cures

• Surgery when a complete resection with negative margins is achievable without loss of function or cosmesis; otherwise biopsy, chemotherapy, then delayed resection.
• Radiotherapy for microscopic or gross residual disease and for all fusion-positive and nodal disease. The classic exception spared radiation is a completely resected (Group I) fusion-negative tumour at a favourable site such as paratesticular.
• Site-specific rules: orbital tumours are treated with chemotherapy plus radiotherapy — orbital exenteration is not the primary approach; bladder/prostate tumours are managed with organ preservation; paratesticular tumours require radical inguinal orchiectomy with high cord ligation.

Contraindicated / avoid

• Transscrotal biopsy or orchiectomy — violates scrotal lymphatics and upstages the radiation field.
• Mutilating upfront debulking, primary amputation, unplanned "shell-out" excision of an undiagnosed mass, and live vaccines during therapy.
• Discuss fertility preservation before gonadotoxic alkylators, per ASCO's fertility preservation guideline.

Disease-related

• Intracranial extension from a parameningeal primary — cranial nerve palsies, meningismus, altered consciousness from skull-base erosion and leptomeningeal seeding. An emergency; requires CSF cytology and urgent radiotherapy planning.
• Airway obstruction (nasopharyngeal/head-and-neck mass) and spinal cord compression (paraspinal extension) — both emergencies.
• Obstructive uropathy from bladder/prostate tumours → hydronephrosis, rising creatinine; obstructive jaundice from biliary primaries.
• Marrow replacement → pancytopenia with a leukoerythroblastic smear, mimicking leukaemia; bone metastases → pain and pathologic fracture.

Treatment-related — acute

• Febrile neutropenia during myelosuppressive chemotherapy: an emergency requiring cultures and empiric antipseudomonal beta-lactam within an hour (IDSA).
• Haemorrhagic cystitis from the cyclophosphamide/ifosfamide metabolite acrolein — gross haematuria; prevented by hydration and mesna.
• Vincristine toxicity: axonal neuropathy with areflexia and foot drop, ileus/severe constipation, jaw pain, and SIADH with hyponatraemia. Intrathecal administration is universally fatal — a never-event.
• Dactinomycin-associated sinusoidal obstruction syndrome (veno-occlusive disease): tender hepatomegaly, weight gain, jaundice and refractory thrombocytopenia — an emergency.
• Ifosfamide: proximal tubulopathy (Fanconi syndrome) and encephalopathy.
• Tumour lysis syndrome with bulky disease — hyperkalaemia, hyperphosphataemia, hyperuricaemia, acute kidney injury.

Treatment-related — late (surveillance per the Children's Oncology Group Long-Term Follow-Up Guidelines)

• Second malignancy: therapy-related AML/MDS from alkylators (typically after a latency of years, with 5q/7q abnormalities) and from topoisomerase II inhibitors (MLL/KMT2A rearrangements, shorter latency); sarcoma or carcinoma within the radiation field, with markedly elevated risk in Li–Fraumeni survivors.
• Anthracycline cardiomyopathy where doxorubicin is used — asymptomatic fall in ejection fraction precedes symptoms, so echocardiographic surveillance is indicated.
• Gonadal failure and infertility from alkylators; growth arrest, facial and orbital hypoplasia, cataract, xerophthalmia and dental abnormalities after head-and-neck radiotherapy; bladder dysfunction after pelvic radiation.

• Sarcoma botryoides = grape-like polypoid mass protruding from the vagina of an infant/toddler (or the cervix of an adolescent — think DICER1). Histology shows the cambium layer of condensed tumour cells beneath intact mucosa. The tumour is embryonal.
• The immunohistochemistry triad is the answer key: desmin, myogenin, MyoD1. Given a small round blue cell tumour, these separate rhabdomyosarcoma from Ewing sarcoma (CD99, EWSR1–FLI1), lymphoma (CD45) and neuroblastoma (synaptophysin, urinary HVA/VMA).
• Fusion, not just histology, sets prognosis: alveolar tumours carry PAX3–FOXO1 t(2;13) or PAX7–FOXO1 t(1;13); they occur in adolescents on extremities/trunk, spread to nodes early, and do worse. Embryonal tumours show LOH at 11p15.5 (the *IGF2*/Beckwith–Wiedemann locus) and do better.
• Single best next step for a suspicious mass: MRI of the primary first, then a planned core/incisional biopsy through a tract the surgeon can later excise — never an unplanned excision and never FNA alone.
• Paratesticular tumour: radical inguinal orchiectomy with high cord ligation. A transscrotal approach is the classic wrong answer — it seeds scrotal lymphatics and enlarges the radiation field.
• Orbital rhabdomyosarcoma causes rapidly progressive proptosis, not leukocoria. Leukocoria is retinoblastoma; periorbital ecchymoses (raccoon eyes) with an abdominal mass is metastatic neuroblastoma.
• Every patient gets chemotherapy (vincristine/dactinomycin/cyclophosphamide backbone in Children's Oncology Group protocols), even after a margin-negative resection — surgery and radiotherapy provide local control only. Orbital disease is treated with chemotherapy plus radiotherapy, not exenteration.
• Association most often tested: rhabdomyosarcoma as a sentinel tumour of **Li–Fraumeni syndrome (TP53); also NF1, Costello (HRAS) and Beckwith–Wiedemann**. A suggestive family history should trigger germline testing referral.