Basics
Description
- A soft tissue cancer with features of skeletal muscle differentiation. Prognostic classification of rhabdomyosarcoma (RMS) currently depends on the following:
- Anatomic site of disease (stage)
- Extent of resection and spread (group)
- Underlying histology (alveolar vs. embryonal or other variants, e.g., botryoid)
Epidemiology
- The most common pediatric soft tissue sarcomas (tumors of mesenchymal origin)
- Accounts for ó ł ╝5% of childhood cancer
- Boys at slightly increased risk compared to girls (incidence by gender of 1.5:1)
- Peaks in children <7 years of age, with another smaller peak in late adolescence
- Median age at diagnosis is 5 years.
Incidence
- 4.5 cases per 1 million children per year
- U.S. annual incidence of about 350 cases per year
Risk Factors
- Radiation exposure, including a possible connection to in utero exposure
- High birth weight associated with embryonal rhabdomyosarcoma in one study.
Genetics
- About 90% of cases are sporadic.
- Several predisposing conditions:
- Li-Fraumeni (autosomal dominant)
- TP53 mutation leads to cancer predisposition through loss of DNA damage signaling.
- Increased risk for soft tissue sarcomas, osteosarcoma, adrenocortical carcinoma, choroid plexus carcinoma, leukemias, breast cancer, and other cancers
- Beckwith-Wiedemann syndrome (sporadic)
- Improper epigenetic regulation of 11p15 leads to an overgrowth syndrome.
- Increased risk of a range of embryonal cancers early in life, including Wilms tumor, hepatoblastoma, and RMS
- Neurofibromatosis type I and Costello syndrome (autosomal dominant)
- Mutational activation of HRAS (Costello) or loss of the RAS-negative regulator NF1 (neurofibromatosis) leads to unchecked RAS signaling and increased risk for RMS.
General Prevention
- No standard approach because most cases are sporadic
- Avoidance of radiation in patients with known predisposing syndromes (e.g., Li-Fraumeni syndrome)
Pathophysiology
- Alveolar rhabdomyosarcomas (ARMS; about 20% of cases) carry translocations t(2;13) or t(1;13) resulting in the fusion transcription factors PAX3-FOXO1 or PAX7-FOXO1.
- Alveolar histology and presence of PAX3-FOXO1 is a poor prognostic factor.
- Animal models combining expression of PAX3-FOXO1 and loss of either TP53 or CDKN2A recapitulate ARMS.
- Embryonal rhabdomyosarcomas (ERMS; about 60% of cases) commonly carry mutations in the RAS pathway as well as loss of heterozygosity at 11p15.
- Animal models of ERMS target activating Ras mutations to myogenic progenitor cells.
- The botryoid subtype of ERMS includes submucosal tumors with a favorable prognosis.
- The remainder of cases include pleomorphic or anaplastic histologies and also harbor a poor prognosis.
Commonly Associated Conditions
- Syndromes listed in "Genetics " Ł have the highest association.
- CNS and genitourinary (GU) anomalies (Chiari malformations, horseshoe kidneys, etc.) in one autopsy-based report
Diagnosis
History
- Often presents as a firm mass that may be painless
- Additional symptoms relate to location of primary mass:
- Orbital (10%): unilateral proptosis, ophthalmoplegia, visual changes
- Head and neck " öparameningeal (16%): sinus pressure, nasal congestion, hypophonation, discharge from the nose or ear, unilateral hearing loss, ophthalmoplegia
- Parameningeal tumors with intracranial extension can present with headache, vomiting, and cranial nerve palsies.
- Head and neck " önonparameningeal (10%; includes scalp, buccal mucosa, face): asymmetric facies, palpable mass
- Extremities (20%): palpable mass, often tender or inflamed
- Genitourinary (25%): bloody or mucous vaginal discharge, prolapse of tissue through vagina or urethra, hematuria, urinary retention, constipation, firm testicular mass
Physical Exam
- Exam findings correlate with sites, as described earlier under "History. " Ł
- Orbital: proptosis; tumor may be visible beneath everted palpebrum
- Head and neck: visibly asymmetric facies. Tumors arising in the sinuses or pharynx may be visible in the oral or nasal cavity.
- Extremities: palpable mass, often tender or inflamed. Lymph nodes commonly involved.
- Genitourinary: Prolapsed tissue may be visible through urethra (bladder primary) or vagina (vaginal primary); firm scrotal mass (paratesticular primary)
- Abnormal neurologic exam raises suspicion for intracranial extension.
- Evidence of cytopenias (petechiae, pallor) raises suspicion for bone marrow metastases.
- Enlarged lymph nodes suggest regional nodal spread, common in extremity RMS.
Diagnostic Tests & Interpretation
Lab
- CBC
- To provide an estimate of marrow involvement
- To help rule out a hematopoietic malignancy
- Electrolytes including calcium and magnesium, liver function tests, and blood urea nitrogen (BUN)/creatinine prior to initiating therapy
- Tumor lysis labs (uric acid, lactate dehydrogenase [LDH] and phosphate in addition to chemistries above) may be helpful if other malignancies are diagnostic considerations.
Imaging
- MRI (preferred) or CT scan of primary site
- Chest CT to rule out pulmonary metastases (most common site of metastatic disease)
- Abdominal and pelvic CT to evaluate for nodal metastases in paratesticular tumors
- 99mTc bone scan and/or PET scan to evaluate for bone metastasis
Diagnostic Procedures/Other
- Surgical biopsy, performed by an experienced surgeon with a high index of suspicion for malignancy and with appropriate precautions to prevent tumor spill
- Bilateral bone marrow biopsies to evaluate for metastatic disease in the bone marrow
- Lumbar puncture for CSF cytology if intracranial extension is a possibility (parameningeal tumors)
- Echocardiogram to ensure normal cardiac function before administering anthracyclines
Alert
Testicular masses should not be biopsied but rather resected along with the spermatic cord through an inguinal approach. It is vital that the performing surgeon is aware of the potential diagnosis of RMS. é á
Pathologic Findings
- Small round blue cells are characteristic, although may see spindle cell elements.
- All RMS are considered high-grade tumors.
- Immunohistochemical stains include positivity for desmin and myogenin, negativity for CD45, CD99, and synaptophysin.
- Diffuse myogenin staining suggests ARMS.
- Fluorescence in situ hybridization (FISH) probes for FOXO1 translocations may help identify ARMS.
Differential Diagnosis
- Other small round blue cell tumors
- Ewing sarcoma (CD99+)
- Neuroblastoma (synaptophysin+)
- Non-Hodgkin lymphoma (CD45+)
- Other cancers
- Non-RMS soft tissue sarcomas
- Germ cell tumors (especially GU masses)
- Rhabdoid tumor
- Nonmalignant masses
- Trauma
- Benign growths (lipoma, rhabdomyoma)
- Abscess or other infectious process
Treatment
Medication
- The backbone of RMS chemotherapy in North America is cycles of vincristine and actinomycin D, with or without cyclophosphamide (also known as "VA " Ł or "VAC " Ł).
- VA can be given as outpatient therapy.
- Cyclophosphamide is omitted for low-risk patients.
- Additional agents under investigation for high risk or relapsed patients include doxorubicin, ifosfamide, etoposide, and camptothecins (e.g., irinotecan).
- Experimental protocols include insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies.
- Supportive care regimens include Pneumocystis carinii pneumonia (PCP) prophylaxis, myeloid growth factors (e.g., granulocyte colony-stimulating factor [G-CSF]) to shorten neutropenia, antiemetics, and laxatives.
Additional Therapies
General Measures
- Therapy usually lasts approximately 1 year.
- Patients require surgery and/or radiation therapy for local control.
- Cytotoxic chemotherapy has significant short- and long-term toxicities (see "Complications " Ł).
- The majority of children are treated at pediatric oncology centers to provide
- Access to the most recent cooperative group clinical trials
- A multidisciplinary team of pediatric oncologists, surgeons, radiation oncologists, pathologists, pharmacists, nutritionists, and social work support
Additional Therapies
- In North America, radiation therapy is used for local control in all cases, except completely resected ERMS.
- Any nonresected sites of metastatic disease are also typically treated with radiation.
Issues for Referral
- Referral to an experienced pediatric oncology center is strongly encouraged.
- A pediatric oncologist should be consulted whenever the diagnosis of RMS is suspected, prior to any invasive procedures.
- Pediatric oncology consultation should also be encouraged for young adults with RMS.
Surgery/Other Procedures
- Surgeons assist in pretreatment staging and in determining a patient 's clinical group based on extent of initial surgery.
- Given radiosensitivity of RMS, avoid surgical procedures that will result in significant loss of function.
- If deemed resectable without significant loss of function, the goal should be complete excision with negative margins.
Inpatient Considerations
- Admit patients with severe cytopenias, threat to vision or airway due to mass effect, or for expedited workup if unable to access care.
- Diagnostic workup can often be performed on an expedited outpatient schedule.
Ongoing Care
Follow-up Recommendations
- Patients seen regularly by pediatric oncology
- After completion of therapy, follow-up with pediatric oncology is every 3 months for the 1st year, then the interval between visits can be gradually increased.
- Patients should continue to receive annual preventive health visits with their primary medical doctor (PMD).
- Vaccinations are deferred during cytotoxic therapy due to limited efficacy, although annual influenza vaccines are recommended.
Patient Education
- Patients ' families are reminded that fevers are medical emergencies in children receiving chemotherapy.
- Patient 's families are advised of signs/symptoms that might suggest recurrent disease.
Prognosis
- Overall survival is approximately 70%, with significant differences based on risk group.
- Current risk stratification in North America includes the following:
- Stage (based on anatomic site of disease, size, and regional node involvement)
- Orbital, nonparameningeal head and neck, vaginal, and biliary tract are favorable.
- Extremity and parameningeal sites are unfavorable.
- Clinical group (extent of residual disease remaining after initial surgery)
- Gross residual disease is unfavorable (except in orbital disease).
- Metastatic disease is very unfavorable.
- Histology
- ARMS is never classified as low risk.
- 5-year event-free survival is estimated to be
- >90% for low-risk disease
- 70 " ô80% for intermediate-risk disease
- <30% for high-risk disease
Complications
- RMS therapy is intensive and has numerous secondary effects.
- Acute toxicities:
- Marrow suppression, requiring blood and platelet transfusions and raising the risk of life-threatening sepsis
- Severe nausea and vomiting
- Mucosal injury with pain and poor PO intake
- Neuropathic pain, extremity weakness, and constipation due to vincristine
- Risk of hemorrhagic cystitis (rare) with cyclophosphamide
- Hepatic sinusoidal obstructive syndrome
- Late effects (see "Cancer Therapy Late Effects " Ł chapter):
- Infertility (related to cyclophosphamide or ifosfamide)
- Cardiomyopathy (related to doxorubicin)
- Secondary malignancies (e.g., leukemia from chemotherapy or sarcomas in radiation field)
- Radiation vasculopathy (increased risk of stroke in patients with CNS radiation, hypertension in those with renal radiation)
- Long-term monitoring in a Cancer Survivorship program is recommended.
Additional Reading
- Hayes-Jordan é áA, Andrassy é áR. Rhabdomyosarcoma in children. Curr Opin Pediatr. 2009;21(3):373 " ô378. é á[View Abstract]
- Huh é áWW, Skapek é áSX. Childhood rhabdomyosarcoma: new insight on biology and treatment. Curr Oncol Rep. 2010;12(6):402 " ô410. é á[View Abstract]
- Malempati é áS, Hawkins é áDS. Rhabdomyosarcoma: review of the Children 's Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer. 2012;59(1):5 " ô10. é á[View Abstract]
- Van Gaal é áJC, De Bont é áES, Kaal é áSE, et al. Building the bridge between rhabdomyosarcoma in children, adolescents, and young adults: the road ahead. Crit Rev Oncol Hematol. 2012;82(3):259 " ô279. é á[View Abstract]
Codes
ICD09
- 71.9 Malignant neoplasm of connective and other soft tissue, site unspecified
- 171.0 Malignant neoplasm of connective and other soft tissue of head, face, and neck
- 171.6 Malignant neoplasm of connective and other soft tissue of pelvis
- 171.5 Malignant neoplasm of connective and other soft tissue of abdomen
ICD10
- C49.9 Malignant neoplasm of connective and soft tissue, unsp
- C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck
- C49.5 Malignant neoplasm of connective and soft tissue of pelvis
- C49.4 Malignant neoplasm of connective and soft tissue of abdomen
SNOMED
- 423610004 Rhabdomyosarcoma of connective or soft tissue
- 254994000 Rhabdomyosarcoma of orbit
- 278024000 Rhabdomyosarcoma of bladder (disorder)
- 302847003 Rhabdomyosarcoma (disorder)
- 404053004 Alveolar rhabdomyosarcoma (disorder)
- 404051002 Embryonal rhabdomyosarcoma (disorder)
FAQ
- Q: Are other children in the family at risk for developing rhabdomyosarcoma?
- A: Familial risk for developing RMS is rare, outside of syndromes addressed in "Genetics. " Ł
- Q: Does a patient 's age influence outcome?
- A: Patients <1 and >10 years of age have poorer outcomes than the majority of RMS patients, who are diagnosed between those ages.