Rhabdomyosarcoma in Children
Rhabdomyosarcoma in Children
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, accounting for approximately 3-4% of all pediatric cancers. It is a malignant tumor that develops from immature cells intended to form skeletal muscle.
Key Points:
- Most common soft tissue sarcoma in children
- Originates from primitive mesenchymal cells
- Can occur in various sites throughout the body
- Requires a multimodal treatment approach
- Prognosis varies widely depending on subtype, location, and stage
Epidemiology
Rhabdomyosarcoma primarily affects children and adolescents, with two peak incidence periods:
- First peak: Between 2-5 years of age
- Second peak: During adolescence
Key Epidemiological Points:
- Incidence: Approximately 4.5 cases per million children/adolescents per year
- Slight male predominance (1.3-1.4:1)
- More common in Caucasian children compared to other racial groups
- Associated genetic syndromes: Li-Fraumeni syndrome, Neurofibromatosis type 1, Costello syndrome
Pathogenesis
The pathogenesis of rhabdomyosarcoma involves complex genetic alterations:
Key Genetic Abnormalities:
- Embryonal RMS: Loss of heterozygosity at 11p15.5
- Alveolar RMS: Chromosomal translocations t(2;13)(q35;q14) or t(1;13)(p36;q14)
These genetic changes lead to the dysregulation of myogenic differentiation and cell proliferation. The PAX3-FOXO1 and PAX7-FOXO1 fusion proteins resulting from these translocations act as aberrant transcription factors, promoting tumor growth and survival.
Classification
Rhabdomyosarcoma is classified into several histological subtypes:
Major Subtypes:
- Embryonal RMS (ERMS): 60-70% of cases
- Botryoid variant
- Spindle cell variant
- Alveolar RMS (ARMS): 20-30% of cases
- Pleomorphic RMS: Rare in children, more common in adults
The 2013 WHO classification also recognizes other rare subtypes such as spindle cell/sclerosing RMS.
Clinical Presentation
The presentation of rhabdomyosarcoma varies widely depending on the primary site of the tumor:
Common Primary Sites:
- Head and neck (40%): Orbit, parameningeal, non-parameningeal
- Genitourinary tract (25%): Bladder, prostate, vagina, uterus
- Extremities (20%)
- Trunk (10%)
- Other sites (5%): Intrathoracic, gastrointestinal
Symptoms:
- Painless mass or swelling
- Proptosis (orbital tumors)
- Nasal or aural discharge (parameningeal tumors)
- Urinary obstruction (genitourinary tumors)
- Constipation or bowel obstruction (pelvic tumors)
- Cranial nerve palsies
- Constitutional symptoms: Fever, weight loss, fatigue
Diagnosis
Diagnosis of rhabdomyosarcoma involves a combination of imaging studies, biopsy, and molecular testing:
Imaging Studies:
- MRI or CT: Primary modality for local staging
- Chest CT: To evaluate for pulmonary metastases
- Bone scan: To assess for bone metastases
- PET-CT: For initial staging and response assessment
Biopsy:
- Core needle biopsy or incisional biopsy: Preferred methods
- Excisional biopsy: May be appropriate for small, superficial lesions
Pathological Examination:
- Light microscopy with H&E staining
- Immunohistochemistry: Desmin, myogenin, MyoD1
- Molecular studies: FISH or RT-PCR for characteristic translocations
Additional Studies:
- Bone marrow aspiration and biopsy
- Lumbar puncture (for parameningeal tumors)
- Lymph node sampling (for extremity tumors)
Primary pulmonary rhabdomyosarcoma
CT scan chest showing mass lesion in the apical segment of right lower lobe.(source)
H and E (original magnification ×400) showing spindle-shaped cells, with a mitotic figure in the center. Few strap cells with bright eosinophilic cytoplasm (arrow).(source)Staging
The current staging system for rhabdomyosarcoma is the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee staging system:
Stage:
- Stage 1: Favorable sites (orbit, head and neck [excluding parameningeal], genitourinary [non-bladder/prostate])
- Stage 2: Unfavorable sites, tumor ≤5 cm, N0
- Stage 3: Unfavorable sites, tumor ≤5 cm, N1, or tumor >5 cm, any N
- Stage 4: Distant metastases
Risk Stratification:
Patients are further classified into low, intermediate, and high-risk groups based on histology, group, stage, and age.
Treatment
Treatment of rhabdomyosarcoma requires a multimodal approach:
Surgery:
- Initial biopsy for diagnosis
- Wide local excision when feasible
- Second-look surgery after chemotherapy
Chemotherapy:
- Backbone: Vincristine, Actinomycin-D, Cyclophosphamide (VAC)
- Additional agents for high-risk disease: Irinotecan, Ifosfamide, Etoposide
Radiation Therapy:
- Local control for unresectable tumors
- Adjuvant therapy for positive margins or node-positive disease
- Dose and timing depend on risk group and response to chemotherapy
Novel Therapies:
- Targeted therapies: IGF-1R inhibitors, mTOR inhibitors
- Immunotherapy: Checkpoint inhibitors
- CAR T-cell therapy: Under investigation
Prognosis
Prognosis for rhabdomyosarcoma varies widely depending on several factors:
Prognostic Factors:
- Histological subtype (ERMS has better prognosis than ARMS)
- Primary site (favorable vs. unfavorable)
- Tumor size and invasiveness
- Presence of metastases
- Age at diagnosis (younger children generally have better outcomes)
- Response to initial therapy
Survival Rates:
- Low-risk: >90% 5-year overall survival
- Intermediate-risk: 60-80% 5-year overall survival
- High-risk: <30% 5-year overall survival
Long-term follow-up is essential due to the risk of late effects from therapy and the possibility of second malignancies.
Rhabdomyosarcoma in Children
- What is the most common soft tissue sarcoma in children?
Rhabdomyosarcoma - What are the two main histological subtypes of rhabdomyosarcoma?
Embryonal and alveolar - Which age group is most commonly affected by embryonal rhabdomyosarcoma?
Children under 5 years old - What is the characteristic genetic alteration in alveolar rhabdomyosarcoma?
PAX3-FOXO1 or PAX7-FOXO1 fusion - Which primary site of rhabdomyosarcoma has the best prognosis?
Orbit - What imaging modality is typically used for initial staging of rhabdomyosarcoma?
CT or MRI of primary site and chest, abdomen, and pelvis - Which chemotherapy drugs form the backbone of rhabdomyosarcoma treatment?
Vincristine, actinomycin D, and cyclophosphamide (VAC) - What is the overall survival rate for localized rhabdomyosarcoma?
70-80% - Which primary site of rhabdomyosarcoma is associated with the worst prognosis?
Parameningeal - What is the name of the staging system used for rhabdomyosarcoma?
Intergroup Rhabdomyosarcoma Study Group (IRSG) staging system - Which syndrome is associated with an increased risk of developing rhabdomyosarcoma?
Li-Fraumeni syndrome - What is the most common site of metastasis in rhabdomyosarcoma?
Lungs - Which immunohistochemical marker is specific for rhabdomyosarcoma?
Myogenin - What is the typical duration of chemotherapy for rhabdomyosarcoma?
40-50 weeks - Which rhabdomyosarcoma subtype has a better prognosis?
Embryonal rhabdomyosarcoma - What is the role of radiation therapy in the treatment of rhabdomyosarcoma?
Used for local control, especially in unresectable tumors - Which molecular pathway is targeted by newer treatments for rhabdomyosarcoma?
IGF1R/PI3K/mTOR pathway - What is the name of the cooperative group that conducts most rhabdomyosarcoma clinical trials in North America?
Children's Oncology Group (COG) - Which imaging modality is used to assess treatment response in rhabdomyosarcoma?
CT or MRI - What is the most common primary site for embryonal rhabdomyosarcoma?
Genitourinary tract - Which histological variant of embryonal rhabdomyosarcoma has the best prognosis?
Botryoid variant - What is the name of the phenomenon where rhabdomyosarcoma cells resemble normal fetal skeletal muscle?
Rhabdomyoblastic differentiation - Which gene is commonly mutated in embryonal rhabdomyosarcoma?
RAS gene family - What is the recommended follow-up imaging for rhabdomyosarcoma survivors?
CT or MRI of primary site and chest imaging - Which late effect is associated with alkylating agent chemotherapy in rhabdomyosarcoma treatment?
Infertility - What is the name of the surgical approach that aims to preserve function in head and neck rhabdomyosarcoma?
Function-preserving surgery - Which molecular test is used to detect PAX-FOXO1 fusion in alveolar rhabdomyosarcoma?
RT-PCR or FISH - What is the most common second malignancy in rhabdomyosarcoma survivors?
Secondary sarcomas - Which growth factor receptor is often overexpressed in rhabdomyosarcoma?
Insulin-like growth factor 1 receptor (IGF1R) - What is the name of the rhabdomyosarcoma subtype that occurs in adults?
Pleomorphic rhabdomyosarcoma
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