Description

Malignant tumor of immature mesenchymal cells committed to skeletal muscle lineage

Epidemiology

• 3rd most common extracranial solid tumor of childhood, after neuroblastoma and Wilms tumor
• ~1.2 times more common in boys than girls

• ~350 new cases are diagnosed each year in the US.
• Most cases (~60–70%) are diagnosed in children <6 years of age.

Risk Factors

Genetics

• Most cases occur sporadically
• Several predisposing conditions:
  • Li–Fraumeni syndrome:
    • Family cancer syndrome associated with germline mutations of the p53 gene (17p13)
    • The syndrome was 1st described after examining the family records of children with rhabdomyosarcoma.
    • Autosomal dominant inheritance
    • Also predisposes to other soft tissue sarcomas, leukemia, brain tumors, adrenocortical carcinoma, and early-onset breast carcinoma
  • Beckwith–Wiedemann syndrome:
    • Fetal overgrowth syndrome characterized by an abnormality at chromosome 11p15
    • Primarily have an increased incidence of Wilms tumor and hepatoblastoma
  • Neurofibromatosis type I:
    • Autosomal-dominant genetic disorder characterized by mutation of the NF1 gene (17q11)
    • Also associated with other soft tissue sarcomas (e.g., malignant nerve sheath tumors, neurofibrosarcomas), leukemia, Wilms tumor, and brain tumors
  • Previous radiation exposure, especially in patients with Li–Fraumeni, neurofibromatosis type I, or hereditary retinoblastoma (RB1 germline mutation)
  • Congenital anomalies of the genitourinary system and CNS are more frequent than expected in children with rhabdomyosarcoma.

Pathophysiology

• 1 of the “small round blue cell” tumors of childhood
• 2 major subtypes:
  • Embryonal (70% of cases):
    • Spindle-shaped cells, less densely cellular with stroma-rich appearance
    • Associated with a chromosomal abnormality at chromosome band 11p15
  • Alveolar (20% of cases):
    • Small round cells with dense appearance lined up along spaces resembling pulmonary alveoli
    • Associated with translocation between chromosomes 2 and 13 (PAX3-FKHR), or less commonly 1 and 13 (PAX7-FKHR)
• Undifferentiated and pleomorphic types comprise the remaining cases.

Etiology

Unknown

Associated Conditions

• Fetal alcohol syndrome
• CNS and genitourinary anomalies
• Tobacco smoking in fathers
• Marijuana and cocaine use in mothers and fathers in the year before child’s birth

Signs and Symptoms

• A painless firm swelling or mass is the most common presentation.
• Other symptoms depend on site of origin:
  • Head/Neck: Nasal congestion or discharge, epistaxis, snoring, sinusitis, dysphagia, otorrhea, chronic otitis media, cranial nerve palsies, proptosis, headache, vomiting, or systemic hypertension (with intracranial growth of tumor)
  • Trunk: Usually few symptoms until tumor widespread
  • Genitourinary/Pelvic: Urinary frequency or retention, hematuria, constipation, vaginal discharge or bleeding
  • Extremity: Painful or painless lumps or erythema

• Condition can occur in any location, even in sites in which skeletal muscle is not normally found.
• Distribution of primary tumor sites include:
  • Head and neck (38%): Parameningeal (e.g., middle ear, nasal cavity, paranasal sinuses, nasopharynx, infratemporal fossa, pterygopalatine fossa, parapharyngeal area), orbit (e.g., orbit, eyelid), nonparameningeal (e.g., scalp, parotid, oral cavity, larynx, oropharynx, cheek, hypopharynx, thyroid, parathyroid, neck)
  • Genitourinary tract (21%): Bladder, prostate, uterus, vagina, vulva, and paratesticular region
  • Extremity (18%)
  • Trunk (7%)
  • Retroperitoneum (7%)
• Special attention should be given during physical examination to lymphatic structures and surrounding tissues, because this may identify local invasion and/or lymphatogenous spread.

Tests

Lab

• CBC
• Electrolytes, liver function tests, and renal function tests in anticipation of starting chemotherapy

• To evaluate primary site and confirm diagnosis: CT scan or, preferably, MRI scan
• To evaluate for evidence of distant metastases (present in 20% of patients at diagnosis):
  • Chest x-ray and CT scan
  • ⁹⁹Tc-diphosphonate bone scan

• Biopsy:
  • Should be performed by an experienced orthopedic surgeon:
    • Avoid contamination of surrounding tissues
    • Ensure adequate tissue sampling to make the diagnosis
  • In addition to routine morphologic and immunohistochemical stain assessments, analysis of tumor genetics by traditional cytogenetics, fluorescent in situ hybridization, or reverse transcriptase–polymerase chain reaction (RT–PCR) is helpful in making the diagnosis and may provide information regarding prognosis.
  • Because of the importance of these studies, consultation with a pediatric oncologist before the biopsy is essential.
• Bilateral bone marrow aspirates and biopsies
• Lumbar puncture for cerebrospinal fluid cytology (parameningeal tumors only; to determine whether CNS is involved)

Differential Diagnosis

• Malignant:
  • Ewing sarcoma
  • Neuroblastoma
  • Non-Hodgkin lymphoma
  • Leukemic chloroma
  • Germ cell tumor
  • Rare soft tissue sarcomas
• Nonmalignant:
  • Trauma
  • Benign tumors: Lipoma, rhabdomyoma, neurofibroma
  • Langerhans cell histiocytosis
  • Abscess

General Measures

• Therapy is multimodal with chemotherapy, radiation therapy, and surgery. Typically structured as:
  • Neoadjuvant chemotherapy
  • Local control (surgery, radiation therapy)
  • Adjuvant chemotherapy
• Most children are treated according to large cooperative group protocols at pediatric oncology centers.
• Treatment is characterized by significant side effects, including increased susceptibility to infection, severe mucositis, and poor nutritional status.
• Experimental therapies such as high-dose chemotherapy with stem cell rescue and immunotherapy (vaccination with fusion-gene peptide products) are being investigated in clinical trials for patients with high-risk or relapsed disease.

Special Therapy

Radiotherapy
Radiation therapy can be used to aid in local control and for control of metastatic disease.

Medication

• Chemotherapy: Common pharmacotherapeutic agents used include vincristine, dactinomycin, cyclophosphamide, doxorubicin, etoposide, and ifosfamide. Other agents (e.g., topotecan, irinotecan) are being investigated.
• Most patients require placement of an indwelling central venous catheter for the duration of their therapy.

Surgery

Trend is toward less radical surgical interventions.

Disposition

Issues for Referral
Consultation with a pediatric oncologist is essential before any attempt is made at a diagnostic biopsy.

Prognosis

• Overall ~70% of patients can be cured.
• Tumor stage and clinical group are used to predict survival and guide therapy:
  • Staging is based on the anatomic site of the tumor and the extent of spread:
    • Favorable sites include: Orbit, nonparameningeal head and neck, nonbladder/prostate genitourinary
    • Unfavorable sites include: Extremities, parameningeal, bladder/prostate
  • Clinical grouping is based on extent of surgical resection. Generally:
    • Stage I: Completely resected
    • Stage II: Gross total resection with microscopic residual disease
    • Stage III: Biopsy only, gross residual disease
    • Stage IV: Distant metastases
• Tumors with alveolar histology (typically extremity lesions) tend to metastasize early.
• The presence of the PAX3-FKHR or PAX7-FKHR gene rearrangement (seen in tumors with alveolar histology) is an adverse prognostic factor, associated with older patients and more advanced disease stage.
• Recurrence can occur many years after completion of therapy but is rare after 3 years.

Complications

• Rhabdomyosarcoma can compromise the function of surrounding organs.
• Metastatic spread may occur to lymph nodes, lung, bone, bone marrow, liver, or brain.
• Acute effects of therapy:
  • Frequent hospital admissions for chemotherapy or complications of that therapy
  • Bone marrow suppression:
    • Transfusions are usually necessary.
    • Neutropenia: Increased risk of bacterial and fungal infections; granulocyte colony-stimulating factor is usually administered daily after chemotherapy to shorten duration of neutropenia.
  • Complications from the GI side effects of chemotherapy or radiotherapy:
    • Nausea and vomiting; relieved with ondansetron and other antiemetic agents
    • Malnutrition secondary to reduced appetite and mucosal ulcerations
• Late effects of therapy:
  • Cardiomyopathy:
    • Anthracyclines (doxorubicin) weaken cardiac muscle, leading to reduced left ventricular function many years after therapy.
    • ~5% of patients receiving cumulative doses of doxorubicin exceeding 500 mg/m² develop CHF.
    • Radiation to the heart can reduce the cumulative dose threshold to 300 mg/m².
  • Kidney and bladder damage:
    • Urinalysis should be performed to detect hemorrhagic cystitis or tubular damage.
    • BP should be monitored in patients who received irradiation to the kidneys; vascular damage and hypertension may develop many years after therapy.
  • Infertility and delayed puberty:
    • Reduced or absent gonadal function is related to high doses of alkylating agents (e.g., cyclophosphamide, ifosfamide): Boys are at high risk of azoospermia; girls may be fertile but are at risk for premature menopause.
    • Low-dose estrogen therapy with oral contraceptive medications may be necessary for amenorrheic women.
  • 2nd malignant neoplasms:
    • Sarcomas may occur within the radiation field.
    • Myelodysplastic syndromes and acute myeloid leukemia may occur secondary to radiation or chemotherapy.
  • Bowel obstruction and enteritis (abdominopelvic tumors):
    • Adhesions as a consequence of surgery or radiation
    • A history of failure to gain weight or symptoms of malabsorption suggest a need for additional evaluation.
  • Growth abnormalities/functional defects at the primary site:
    • Radiation doses >20 Gy will cause growth retardation in prepubertal children.
    • Scoliosis can occur if the vertebrae are involved in the radiation field.
    • Cataracts can occur after irradiation involving the head.
  • Learning difficulties: Radiotherapy directed to the CNS in children younger than 3 years old with head/neck primary cancers may produce significant cognitive deficits.

ICD-9

171.9 Malignant neoplasm of connective and other soft tissue, site unspecified

FAQ

• Q: Can a child with rhabdomyosarcoma attend school?
• A: Because chemotherapy for rhabdomyosarcoma is intensive, many children are unable to continue with school during this time but benefit from educational instruction at home.
• Q: Is the treatment associated with infertility?
• A: The present chemotherapy regimens include high cumulative doses of alkylating agents placing boys, in particular, at high risk for infertility. Sperm banking is recommended for adolescent boys before starting chemotherapy.

AUTHOR

Edward F. Attiyeh, MD

BIBLIOGRAPHY

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