Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric oncologist/hematologist, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ summary on Pediatric Supportive Care for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For rhabdomyosarcoma, the 5-year survival rate increased over the same time, from 53% to 67% for children younger than 15 years and from 30% to 51% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Incidence and Epidemiology
Childhood rhabdomyosarcoma, a soft tissue malignant tumor of mesenchymal origin, accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years.[3,4] The incidence is 4.5 per 1 million children and 50% of cases are seen in the first decade of life.
Incidence may depend on the histologic subtype of rhabdomyosarcoma:
- Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (M:F = 1.5) and peaks in the 0 to 4 year age group at approximately 4 cases per 1 million children, with a lower rate in adolescents, approximately 1.5 cases per 1 million adolescents.
- Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by gender and is constant from ages 0 to 19 years at approximately 1 case per 1 million children and adolescents.
- Undifferentiated sarcoma: Infants younger than 1 year have a higher incidence of undifferentiated sarcoma and tumors of the trunk and abdomen and a lower incidence of parameningeal tumors than do older patients.
The most common primary sites for rhabdomyosarcoma are the head, the genitourinary tract, and the extremities.[7,8] Within extremity tumors, tumors of the hand and foot occur more often in older patients and have an alveolar histology; these tumors also have a higher rate of metastatic spread. Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen including the retroperitoneum and biliary tract.
Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing factor or risk factor. For patients with embryonal tumors, high birth weight and large size for gestational age are associated with an increased incidence of rhabdomyosarcoma. Genetic conditions associated with rhabdomyosarcoma include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations),[12-14] pleuropulmonary blastoma (with DICER1 mutations),[15,16] neurofibromatosis type I, Costello syndrome (with germline HRAS mutations),[18-21] Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated),[22,23] and Noonan syndrome.[21,24,25]
The prognosis for a child or adolescent with rhabdomyosarcoma is related to the age of the patient, site of origin, tumor size (widest diameter), resectability, presence of metastases, number of metastatic sites or tissues involved, presence or absence of regional lymph node involvement, histopathologic subtype (alveolar vs. embryonal), and delivery of radiation therapy in selected cases,[7,8,26-32]; [Level of evidence: 3iiiA] as well as unique biological characteristics of rhabdomyosarcoma tumor cells. It is unclear whether response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, because the Intergroup Rhabdomyosarcoma Study Group (IRSG) and Children's Oncology Group studies found no association.; [Level of evidence: 3iiDi] However, an Italian study found that patient response did correlate with likelihood of survival.[Level of evidence: 3iiA]
Rhabdomyosarcoma is usually curable in most children with localized disease who receive combined-modality therapy, with more than 70% surviving 5 years after diagnosis.[7,8,38] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common in patients who have gross residual disease in unfavorable sites after initial surgery and in those who have metastatic disease at diagnosis.
Examples of both clinical and biological factors with proven or possible prognostic significance include the following:
- Age: Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent IRSG trials, 5-year failure-free survival (FFS) was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. Five-year survival for these groups was 76%, 87%, and 76%, respectively. Historical data show that adults fare worse than children (5-year overall survival (OS) rates, 27% ± 1.4% and 61% ± 1.4%, respectively; P < .0001).[40-43]
- Infants may do poorly because their bone marrow is less tolerant of chemotherapy doses that older children can receive; thus, infants are relatively underdosed compared with older patients. In addition, infants younger than 1 year may be less likely to receive radiation therapy for local control, because of concern about the high incidence of complications in this age group. [27,38,44] Thus, they have a relatively high rate of local failure.
- In older children, vincristine and dactinomycin have upper dosage limits based on body surface area, and these patients may also require reduced vincristine doses because of neurotoxicity.[27,45]
- Adolescents: A report from the AIEOP (Italian) Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease involvement, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival rates were somewhat lower in adolescents than in children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years.
- Site of origin: Primary sites with more favorable prognoses include the following:[7,8,47,48]
- Orbit and nonparameningeal head and neck.
- Paratestis, vulva, vagina, uterus (nonbladder, nonprostate genitourinary tract).
- Biliary tract.
- Diameter of the tumor: Patients with smaller tumors (≤5 cm) have improved survival compared with children with larger tumors. Both tumor volume and maximum tumor diameter are associated with outcome.[Level of evidence: 3iiA]
A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area (BSA). This was not confirmed by a Children's Oncology Group study of patients with intermediate-risk rhabdomyosarcoma. This relationship requires prospective study to determine the therapeutic implications of the observation.
- Metastases and regional lymph node involvement: Children with metastatic disease at diagnosis have the worst prognosis. The prognostic significance of metastatic disease is modified by tumor histology (embryonal is more favorable than alveolar), the site of metastatic disease, and the number of metastatic sites.[28,51,52] Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than do patients with metastatic disease from primary tumors at other sites.
- Resectability: The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, formerly called the Clinical Group) is also correlated with outcome. In the IRS-III study, patients with localized, gross residual disease after initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of approximately 70%, compared with a more than 90% 5-year survival rate for patients without residual tumor after surgery (Group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor after surgery (Group II).[7,26] Regardless, outcome is primarily related to the use of multimodality therapy; all patients require chemotherapy and at least 85% also benefit from radiation therapy, with favorable outcome even for those patients with nonresectable disease. In IRS-IV, the Group III patients with unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS of about 75%.
- Histopathologic subtype: The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity primary tumors, and metastatic disease at diagnosis), and is generally associated with a worse outcome than in similar patients with embryonal rhabdomyosarcoma. In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I). A statistically significant difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma), was not noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed. In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the alveolar patients received more intensive therapy.
Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year FFS, 43%) than patients who do not have regional lymph node involvement (5-year FFS, 73%).
Anaplasia has been observed in 13% of cases of rhabdomyosarcoma and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).
- Biological characteristics: Refer to the Molecular Classification section of this summary for more information.
- Response to therapy: In a study of 94 patients with rhabdomyosarcoma who underwent preirradiation and postirradiation positron emission tomography (PET) imaging at a median of 55 days after the completion of radiation therapy, a negative postirradiation PET predicted improved local failure-free survival. This difference was most pronounced for patients who had a negative postirradiation PET and no evidence of residual disease on coregistered computed tomography.
Adult patients with rhabdomyosarcoma have a high incidence of pleomorphic histology (19%). Pleomorphic histology is extremely rare in children and young adults with rhabdomyosarcoma. Adults also have a higher incidence of tumors in unfavorable sites than do children.
Because treatment and prognosis depend, in part, on the histology and molecular genetics of the tumor, it is necessary that the tumor tissue be reviewed by pathologists and cytogeneticists/molecular geneticists with experience in the evaluation and diagnosis of tumors in children. Additionally, the diversity of primary sites, the distinctive surgical and radiation therapy treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.
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