What are the symptoms, diagnosis, and treatment options for Rhabdomyosarcoma (RMS)?

Rhabdomyosarcoma (RMS): Comprehensive Clinical Overview

Clinical Presentation and Symptoms

RMS typically presents as an unexplained soft tissue mass, with symptoms varying by anatomic location and disease extent. 1

Primary Presentation

• Any unexplained deep soft tissue mass or superficial lesion >5 cm warrants immediate referral to a sarcoma reference center 1
• Most common sites include head and neck (52%), trunk (26%), genitourinary system, and extremities (7%) 2, 3
• Patients may present with bone pain, deterioration of performance status, or persistent cough in advanced stages 4

Site-Specific Symptoms

• Head and neck lesions: mass effect, cranial nerve deficits, nasal obstruction
• Genitourinary: hematuria, urinary obstruction, vaginal bleeding or mass
• Extremity: palpable mass with or without pain
• Unusual presentation: massive bone marrow infiltration mimicking hematologic malignancy with fatigue, myalgia, bruising, petechiae, and cytopenias 5

Metastatic Disease Indicators

• Alveolar RMS (ARMS) with T2 tumors shows significantly higher metastatic rates: 13% lung metastases and 23% bone marrow involvement 6
• Regional lymph node involvement occurs in approximately 33% at presentation 2

Diagnostic Evaluation

Multiple core needle biopsies using needles >16G under imaging guidance are the standard diagnostic approach, avoiding necrotic areas and planning the biopsy tract for safe removal during definitive surgery. 1

Tissue Diagnosis

• Core needle biopsy is preferable to fine needle aspiration, with diagnostic accuracy of 87% when immunocytochemistry is utilized 7
• Samples must be fixed in formalin; avoid Bouin fixation as it prevents molecular analysis 1
• Immunohistochemistry and cytogenetics are mandatory to identify embryonal vs. alveolar subtypes 1
• Molecular pathology (FISH, RT-PCR) should complement morphology when clinical-pathological presentation is unusual 1

Imaging Studies

• MRI with contrast enhancement is the preferred imaging modality for extremity and trunk wall tumors 1
• Plain radiographs should be obtained first to rule out bone tumors, detect bone erosion, and identify calcifications 1
• Chest CT scan is mandatory for staging to exclude pulmonary metastases 1
• Abdominal/pelvic CT should be considered for specific histologic subtypes with high metastatic potential 1

Risk-Stratified Staging Evaluation

• For embryonal RMS (ERMS) with T1 tumors: minimal staging evaluation is recommended, omitting bone marrow aspirate/biopsy and bone scan due to 0% rate of bone/bone marrow involvement 6
• For alveolar RMS (ARMS) with T2 tumors: aggressive staging evaluation including bone marrow assessment is required 6

Prognostic Factors

T stage is the single most significant predictor of outcome, followed by M stage, clinical grouping, primary tumor site, patient age, and histologic subtype. 6

Treatment Approach

Multidisciplinary Management

RMS requires management by a formally constituted sarcoma multidisciplinary team (MDT) at a reference center treating high volumes of patients. 4, 1

Localized Disease Treatment Algorithm

1. Surgery

Surgery is the standard treatment for all patients with localized disease, performed by a surgeon specifically trained in sarcoma management. 4, 1, 8

• The primary aim is complete excision with a margin of normal tissue through en bloc resection via grossly normal tissue planes 8
• The tumor should be removed by wide excision or compartmental resection, including the cutaneous scar and biopsy tract 1, 8
• Re-operation is recommended in cases of previous marginal or intralesional resection 1, 8
• Positive margins (R1/R2) mandate re-excision if functionally feasible 8
• Functional limb preservation is the goal; amputation is reserved only when complete resection would render the limb non-functional 8

2. Chemotherapy

All patients with RMS should receive chemotherapy, either at diagnosis in advanced/metastatic stages or after initial resection in early local stages. 3

For rhabdomyosarcoma specifically, the FDA-approved regimen is dactinomycin 15 mcg/kg intravenously once daily for 5 days every 3 to 9 weeks for up to 112 weeks, as part of a multi-agent combination chemotherapy regimen. 9

• Patients whose disease responds to chemotherapy have significantly better metastasis-free survival (72% at 10 years) compared to non-responders (19% at 10 years) 2
• Response evaluation should be performed after 2 or 3 cycles with the radiological exams that were positive before treatment 1

3. Radiation Therapy

After wide excision of high-grade sarcomas, adjuvant radiation therapy is recommended. 1, 8

• Standard postoperative radiation dose: 50-60 Gy in fractions of 1.8-2 Gy, with possible boosts up to 66 Gy depending on presentation and quality of surgery 1
• Preoperative radiotherapy: 50 Gy 1
• For hypofractionated regimens: 50 Gy in 20 fractions (2.5 Gy per fraction) 1
• For compromised margins: additional boost of 16-18 Gy for microscopically positive margins and 20-26 Gy for macroscopic residual disease 1
• Surgery should be performed 4-8 weeks after completion of preoperative radiotherapy 1
• During concomitant radiation, reduce dactinomycin dose by 50% 9

Metastatic Disease

Chemotherapy is the standard treatment for metastatic disease, with doxorubicin with or without ifosfamide commonly used. 1

• In cases of completely resectable lung metastases, surgery should be considered 1
• Nearly one-third of patients with localized RMS and over two-thirds with metastatic RMS will experience disease recurrence, generally within three years 10

Relapsed Disease

Patients with botryoid RMS or stage 1/group I embryonal RMS who have had no prior cyclophosphamide treatment have the highest chance of achieving long-term cure with multiagent chemotherapy at relapse. 10

• Tissue biopsy confirmation of relapse diagnosis is essential 10
• For patients not meeting favorable criteria (representing the majority), strong consideration should be given for enrollment in clinical trials 10

Follow-Up Protocol

Patients should be followed every 3 months with history and physical examination. 1

• MRI of the resection site: twice yearly for the first 2-3 years, then once yearly 1
• For high-grade tumors, chest X-ray: every 3-4 months in the first 2-3 years, twice yearly up to the 5th year, and once yearly thereafter 1

Critical Pitfalls to Avoid

• Never perform definitive resection without expert pathology confirmation via core needle biopsy 8
• Never accept positive margins without attempting re-excision, as this significantly impacts survival 8
• Never perform surgery outside a multidisciplinary sarcoma team 8
• Never use live viral vaccines before or during treatment 9
• Never administer dactinomycin within two months of radiation without dose reduction due to radiation recall risk 9

Prognosis

• 10-year actuarial disease-free and overall survival rates for adult RMS are 41% and 40%, respectively 2
• The major determinant of metastatic control and survival is primary tumor size (≤5 cm vs. >5 cm) 2
• Local control is satisfactory (87% at 10 years) for sites other than parameningeal (50% at 10 years) 2