General Information About Childhood Rhabdomyosarcoma

Continual improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1,2,3] Between 1975 and 2017, the 5-year relative survival rate for patients with rhabdomyosarcoma increased from 53% to 71% for children younger than 15 years and from 30% to 52% for adolescents aged 15 to 19 years.[1,2] In more recent years, improvements in outcome have plateaued.

Childhood and adolescent cancer survivors require close monitoring because side effects of cancer and its therapy may persist or develop months to years later. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Incidence

Childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin. It accounts for approximately 2.7% of cancer cases among children aged 0 to 14 years and 1.4% of the cases among adolescents and young adults aged 15 to 19 years.[2] The incidence is 4.6 cases per 1 million children younger than 20 years, which translates into about 350 new cases per year. Fifty percent of these cases are seen in the first decade of life.[2,4]

The 2020 World Health Organization classification distinguishes four histological subtypes of rhabdomyosarcoma, including embryonal, alveolar, spindle cell/sclerosing, and pleomorphic.[5] While these subtypes classify rhabdomyosarcoma into prognostically useful histological categories, FOXO1 gene fusions uniquely occur in alveolar histology tumors; however, not all tumors that have been classified as alveolar histology have a FOXO1 fusion. Molecular characterization has replaced histopathological assessment for treatment risk assignment. Male patients have a higher incidence of embryonal tumors, and Black patients have a slightly higher incidence of alveolar tumors.[4] For more information, see the sections on Cellular Classification for Childhood Rhabdomyosarcoma and Molecular Characteristics of Rhabdomyosarcoma.

Incidence may depend on the histological subtype of rhabdomyosarcoma, as follows:

• Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (male-to-female ratio, 1.5). The peak incidence is in children between the ages of 0 and 4 years, with approximately 4 cases per 1 million children. The incidence rate is lower in adolescents, with approximately 1.5 cases per 1 million adolescents. This subtype constitutes 57% of patients in the Surveillance, Epidemiology, and End Results (SEER) Program database.[4]
• Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by sex and is constant from ages 0 to 19 years, with approximately 1 case per 1 million children and adolescents. This subtype constitutes 23% of patients in the SEER database.[4]
• Spindle cell/sclerosing: Spindle cell and sclerosing rhabdomyosarcoma are considered in the same diagnostic category. This uncommon variant accounts for 3% to 10% of all cases.[5]
• Pleomorphic: Pleomorphic rhabdomyosarcoma is a high-grade pleomorphic sarcoma seen in adults. Childhood cases are considered to be rhabdomyosarcoma with diffuse anaplasia.[5]

Rhabdomyosarcoma may occur anywhere in the body. The most common primary sites include the following:[6,7]

• Head and neck region (parameningeal) (approximately 25%).
• Genitourinary tract (approximately 31%).
• Extremities (approximately 13%). Within extremity tumors, tumors of the hand and foot occur more often in older patients and usually have an alveolar histology.[8]

Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract.[7]

Risk Factors

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor.

Predisposition factors reported for rhabdomyosarcoma include the following:

• Genetic factors:
  • Li-Fraumeni cancer susceptibility syndrome (with germline TP53 variants).[9,10,11]
  • DICER1 syndrome.[12,13]
  • Neurofibromatosis type I (NF1).[14,15]
  • Costello syndrome (with germline HRAS variants).[16,17,18,19]
  • Beckwith-Wiedemann syndrome (more commonly associated with Wilms tumor and hepatoblastoma).[20,21]
  • Noonan syndrome.[19,22,23]
• High birth weight and large size for gestational age are associated with an increased incidence of embryonal rhabdomyosarcoma.[24]

The Children's Oncology Group (COG) performed retrospective exome sequencing on germline DNA to determine the prevalence of 63 autosomal dominant cancer-predisposing genes in 615 patients with newly diagnosed rhabdomyosarcoma.[25] They identified germline cancer-predisposition variants in 45 patients with rhabdomyosarcoma (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes. Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric rhabdomyosarcoma risk, such as Li-Fraumeni syndrome (TP53, n = 11) and NF1 (NF1, n = 9). Notably, five patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome, and two patients each had variants in DICER1 and CBL, respectively. Germline variants were more frequent in patients with embryonal rhabdomyosarcoma than in those with alveolar rhabdomyosarcoma (10% vs. 3%, P = .02), but all of the patients with alveolar rhabdomyosarcoma were FOXO1 negative, and no germline variants were identified in patients with FOXO1 translocations. Although patients with a cancer-predisposition variant tended to be younger at diagnosis (P = .00099), 40% of germline variants were identified in patients older than 3 years.

The COG reviewed the impact of germline variants in cancer predisposition genes on patient outcomes.[26] In this study of 580 individuals with rhabdomyosarcoma, the median age was 5.9 years (range, 0.01–23.23 years), and the male-to-female ratio was 1.5:1 (351 [60.5%] male). For patients with congenital variants in rhabdomyosarcoma-associated cancer-predisposition genes, the event-free survival (EFS) rate was 48.4%, compared with 57.8% for patients without congenital predisposition variants (P = .10). The overall survival (OS) rate was 53.7% for patients with congenital predisposition variants, compared with 65.3% for patients without these variants (P = .06). Analyses were stratified by tumor histology and PAX3::FOXO1 or PAX7::FOXO1 gene fusion status. After adjustment, patients with congenital predisposition variants had significantly worse OS (adjusted hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.39–4.45; P = .002), and patients with embryonal histology did not have better outcomes (EFS: adjusted HR, 2.25; 95% CI, 1.25–4.06; P = .007 and OS: adjusted HR, 2.83; 95% CI, 1.47–5.43; P = .002). These associations were not due to the development of a second malignant neoplasm. In addition, patients with fusion-negative rhabdomyosarcoma who harbored congenital predisposition variants had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma who did not have congenital predisposition variants (EFS: adjusted HR, 1.35; 95% CI, 0.71–2.59; P = .37 and OS: adjusted HR, 1.71; 95% CI, 0.84–3.47; P = .14).

The COG reviewed the correlation between anaplastic histology and germline TP53 pathogenic variants in 239 patients with rhabdomyosarcoma. Among the 46 patients with anaplastic rhabdomyosarcoma, 11% (n = 5) carried a germline TP53 pathogenic variant, compared with 1% (n = 2) of the patients without anaplasia (P = .003). The rates of TP53 pathogenic variants in those with diffuse anaplasia and focal anaplasia were 9% (n = 3) and 17% (n = 2), respectively. Among the seven patients with TP53 pathogenic variants, 71% (5 of 7) had tumors with anaplastic histology.[27]

Prognostic Factors

Rhabdomyosarcoma is usually curable in children with localized disease who receive combined-modality therapy, with more than 70% of patients surviving 5 years after diagnosis.[6,7,28] Relapses are uncommon in patients who were alive and event free at 5 years, with a 10-year late-event rate of 9%. Relapses are more common in patients who have unresectable disease, tumor in an unfavorable site at diagnosis, or metastatic disease at diagnosis.[29]

The prognosis for children or adolescents with rhabdomyosarcoma is related to many clinical and biological factors, including the following:

• Age.
• Site of origin.
• Tumor size.
• Resectability.
• Histopathological subtype.
• PAX3::FOXO1 or PAX7::FOXO1 gene fusion status.
• Metastases at diagnosis.
• Lymph node involvement at diagnosis.
• Biological characteristics.
• Response to therapy.
• Circulating tumor DNA and RNA.

Because treatment and prognosis partly depend on the histology and molecular characterization of the tumor, it is necessary that the tumor tissue be reviewed by expert pathologists with experience in the evaluation and diagnosis of tumors in children. Typically, accurate diagnosis requires additional molecular characterization. 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.

Age

Children aged 1 to 9 years have the best prognosis, while those younger than 1 year and older than 10 years fare less well. In Intergroup Rhabdomyosarcoma Study Group (IRSG) and COG trials, the 5-year failure-free survival (FFS) rate was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. The 5-year OS rates were 76% for patients younger than 1 year, 87% for patients aged 1 to 9 years, and 76% for patients older than 10 years.[30] Historical data show that adults have fared less well than children (5-year OS rates, 27% ± 1.4% vs. 61% ± 1.4%; P < .0001).[31,32,33,34]

• Young age: Infants tend to do poorly, often because of treatment modifications to reduce toxicity. Typically, chemotherapy doses are reduced by 50% on the basis of reports that infants have higher death rates related to chemotherapy toxicity when compared with older patients; therefore, young patients may be underdosed.[35] In addition, infants younger than 1 year are less likely to receive radiation therapy for local control because of the high incidence of late effects in this age group.[28,36,37]

  The 5-year FFS rate was 67% for infants, compared with 81% in a matched group of older patients treated by the COG.[30,38] This inferior FFS rate was largely the result of a relatively high rate of local failure.

  In another retrospective study of 126 patients (aged ≤24 months) who were enrolled on the ARST0331 (NCT00075582) and ARST0531 (NCT00354835) trials, the 5-year local failure rate was 24%, the 5-year EFS rate was 68.3%, and the OS rate was 81.9%. Forty-three percent of the patients had an individualized local therapy plan that more frequently omitted radiation therapy. These patients had inferior local control and EFS rates.[38]

  Members of the Cooperative Weichteilsarkom Studiengruppe (CWS) reviewed 155 patients with rhabdomyosarcoma presenting from birth to age 12 months; 144 patients had localized disease; 11 patients had metastases; and 32 patients presented with alveolar rhabdomyosarcoma pathology. The following results were reported:[39][Level of evidence C1]

  • Of the 144 patients with localized disease, 129 had a complete response.
  • Fifty-one infants had a recurrence of their disease; 63% of patients with alveolar rhabdomyosarcoma had a relapse, and 28% of patients with embryonal rhabdomyosarcoma had a relapse.
  • The 5-year OS rates were 69% for patients with localized disease, 14% for patients with metastatic disease, and 41% for patients with relapsed disease.

  A retrospective analysis of five consecutive studies from the CWS group examined infants and older children with localized rhabdomyosarcoma of the female genitourinary tract.[40] Among 67 patients treated from 1981 to 2019, age of 12 months or younger at diagnosis was the only significant negative prognostic factor that influenced EFS.

  The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) enrolled 490 children younger than 36 months in their prospective RMS2005 study. The study included 110 patients younger than 12 months and 380 patients aged 12 to 36 months. Chemotherapy was given according to the risk group. Radiation therapy (22% received brachytherapy) was administered to 33.6% of the infants and 63.5% of the children aged 12 to 36 months. The 5-year OS rate was 88.4% for the infants, which was significantly better than the 72.5% rate observed in children aged 12 to 36 months. The treatment protocol in this trial, which used an increased application of adequate local therapy, may have contributed to these improved outcomes.[41][Level of evidence B4]

  The EpSSG analyzed neonates with congenital rhabdomyosarcoma, which they defined as infants younger than 2 months at diagnosis who were enrolled in EpSSG trials.[42] Twenty-four patients with congenital rhabdomyosarcoma were registered. All patients had favorable histology and localized disease, except for one patient with PAX3::FOXO1 fusion–positive metastatic rhabdomyosarcoma. Three patients had VGLL2::CITED2 or VGLL2::NCOA2 fusions. Complete tumor resection was achieved in ten patients. No radiation therapy was given. Chemotherapy doses were adjusted to age and weight. Only two patients required further dose reduction for toxicity. The 5-year EFS rate was 75.0% (95% CI, 52.6%–87.9%), and the OS rate was 87.3% (95% CI, 65.6%–95.7%).

  An international consortium identified 40 infants with spindle cell rhabdomyosarcoma.[43] The 5-year EFS rate for these infants with localized disease was 86% (± 11%; 95% CI), and the OS rate was 91% (± 9%; 95% CI). These outcomes compare favorably with those of all infants with localized rhabdomyosarcoma, for whom the 5-year failure-free survival rates range from 42% to 72% and the 5-year OS rates range from 61% to 88%. This finding suggests that infants with congenital spindle cell rhabdomyosarcoma have a favorable outcome compared with infants with other subtypes of rhabdomyosarcoma.

• Older children: In older children, the upper dosage limits of vincristine and dactinomycin are based on body surface area (BSA), and these patients may require reduced vincristine doses because of neurotoxicity.[37,44]
• Adolescents: A report from the Associazione Italiana Ematologia Oncologia Pediatrica Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease at diagnosis, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival (PFS) 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.[45]

  Two reports from the COG have documented inferior 5-year EFS rates in patients older than 10 years.[37,44] When compared with younger patients, this group of older patients was more likely to present with advanced-stage, large, and invasive alveolar tumors, with nodal involvement arising in the extremity and paratesticular sites. Older patients experienced less myelosuppression and more peripheral nervous system toxicity, suggesting that dose modifications during therapy cannot account for the age-related differences in EFS.

  Adolescent and young adult (AYA) patients were more likely to have worse survival outcomes than children.[46]

  • AYA patients were more likely to have metastatic tumors (61 of 257 [23.7%] vs. 197 of 1,720 [11.5%]; P < .0001), unfavorable histological subtypes (119 [46.3%] vs. 451 [26.2%]; P < .0001), tumors larger than 5 cm (177 [68.9%] vs. 891 [51.8%]; P < .0001), and regional lymph node involvement (109 [42.4%] vs. 339 [19.7%]; P < .0001) than children.
  • AYA patients had lower 5-year EFS rates (52.6% [95% CI, 46.3%–58.6%] vs. 67.8% [95% CI, 65.5%–70.0%]; P < .0001) and OS rates (57.1% [95% CI, 50.4%–63.1%] vs. 77.9% [95% CI, 75.8%–79.8%]; P < .0001) than children.
  • The multivariable analysis confirmed the inferior prognosis of patients aged 15 to 21 years (HR, 1.48 [95% CI, 1.20–1.83; P = .0002] for poorer EFS; HR, 1.73 [95% CI, 1.37–2.19; P < .0001] for poorer OS).
• Adults: Adult patients with rhabdomyosarcoma have a higher incidence of pleomorphic histology (19%) than do children (<2%). Adults also have a higher incidence of tumors in unfavorable sites than do children.[31]

Site of origin

Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site (see Table 1).

Tumor size

Children with tumors 5 cm or smaller have improved survival, compared with children with tumors larger than 5 cm.[6] Both tumor volume and maximum tumor diameter are associated with outcome.[54][Level of evidence C1]

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 BSA.[55] This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma.[56] This relationship requires prospective study to determine the therapeutic implications of the observation.

Resectability

The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, also called the Clinical Group) is correlated with outcome.[6] 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 rate of more than 90% for patients without residual tumor after surgery (Group I) and a rate of approximately 80% for patients with microscopic residual tumor after surgery (Group II).[6,57] Groups I and II represent a minority of patients; approximately 50% of patients have unresectable Group III disease at time of diagnosis.[6]

Resectability without functional impairment is related to the tumor's initial size and site and does not account for the biology of the disease. Outcome is optimized with the use of multimodality therapy. All patients require chemotherapy, and at least 85% of patients also benefit from radiation therapy, with favorable outcomes even for patients with nonresectable disease. In the IRS-IV study, the Group III patients with localized unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS rate of about 75% and a local control rate of 87%.[58] Two intermediate-risk COG rhabdomyosarcoma studies (D9803 and ARST0531 [NCT00354835]) were pooled to assess the benefit of delayed primary excision. In the D9803 study, local control with radiation therapy after either a partial or complete excision was completed at week 12. In the ARST0531 study, radiation was administered upfront at week 4. Patients with bladder or prostate rhabdomyosarcoma who received a delayed primary excision had no difference in survival, whereas patients with extremity rhabdomyosarcoma or nonbladder/nonprostate nonextremity rhabdomyosarcoma had an improved OS with delayed primary excision. Delayed primary excision strategy with a reduction in radiation dose resulted in superior OS for those sites.[59,60]

Histopathological subtype

The alveolar subtype of childhood rhabdomyosarcoma is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity and truncal primary tumors, and metastatic disease at diagnosis). It 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).[61]
• A statistically significant difference in 5-year survival by histopathological subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma) was noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[62]
• In the IRS-III study, the 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.[6]
• Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes than patients who do not have regional lymph node involvement (5-year FFS rates, 43% vs. 73%).[63]
• Local-control rates after radiation therapy are similar among patients with alveolar and embryonal tumors. However, patients who present with tumors 5 cm or larger have a significantly higher local failure rate.[64]

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases, with some studies suggesting the presence of anaplasia adversely influenced clinical outcome in patients with intermediate-risk disease. However, anaplasia has not been shown to be an independent prognostic variable.[65,66]

PAX3::FOXO1orPAX7::FOXO1gene fusion status

Approximately 80% of rhabdomyosarcoma cases morphologically defined as alveolar rhabdomyosarcoma express a FOXO1 fusion. FOXO1 gene fusions occur only in alveolar histology tumors.[67] Several retrospective studies found that fusion status is an independent prognostic factor. Patients with translocation-negative alveolar rhabdomyosarcoma have tumors with genetic and molecular profiles and outcomes similar to patients with embryonal rhabdomyosarcoma, and they fare better than patients with fusion-positive alveolar rhabdomyosarcoma.[68,69] Early retrospective studies relied on convenience samples of available tumor tissue.[68,69] A subsequent prospective study from the Soft Tissue Sarcoma Committee of the COG that examined 434 cases of intermediate-risk rhabdomyosarcoma treated on a single intermediate protocol (D9803) confirmed these observations.[70] Analysis of 38 patients enrolled in the COG D9802 (NCT00003955) low-risk study determined that fusion-positive, low-risk patients should be treated as intermediate risk.[71]

The specific fusion partner may have prognostic impact. In a COG study, fusion-positive patients with Stage 2 or 3, Group III, and PAX3-positive tumors had a lower EFS rate (54%) than those with PAX7-positive tumors (65%). Both fusion-positive groups did worse than those with embryonal rhabdomyosarcoma (EFS rate, 77%; P < .001). Patients with alveolar rhabdomyosarcoma and PAX3 fusions had a poorer OS rate (64%) than patients with alveolar rhabdomyosarcoma and PAX7 fusions (87%), patients with alveolar rhabdomyosarcoma who were fusion negative (89%), and patients with embryonal rhabdomyosarcoma (82%; P = .006).[70] Comparable results were observed in the U.K. study; patients with PAX7-positive tumors and patients with fusion-negative tumors had similar outcomes.[72]

Using data from six consecutive COG studies, a retrospective analysis of 1,727 patients with rhabdomyosarcoma refined the risk stratification for childhood rhabdomyosarcoma. The study reported that after metastatic status, FOXO1 status was the most important prognostic factor and improved the risk stratification of patients with localized rhabdomyosarcoma.[69]

The COG performed a retrospective analysis of 269 patients with confirmed FOXO1 fusion–positive rhabdomyosarcoma who were enrolled in three completed clinical trials for localized rhabdomyosarcoma.[73] The estimated 4-year EFS rate was 53% (95% CI, 47%–59%), and the OS rate was 69% (95% CI, 63%–74%). Multivariate analysis identified older age (≥10 years) and larger tumor size (>5 cm) as independent, adverse prognostic factors for EFS within this population. Patients who had both of these adverse features experienced substantially inferior outcomes.

An EpSSG study evaluated the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma, using data from the EpSSG RMS2005 study. The multivariable analysis of 1,661 evaluable patients retained five prognostic variables: age at diagnosis, tumor size, primary site, IRS Group, and FOXO1 status. A nomogram was created, stratifying patients into four risk groups. The 5-year EFS rates were 94.1% for patients in the low-risk group, 78.4% for patients in the intermediate-risk group, 65.2% for patients in the high-risk group, and 52.1% for patients in the very high-risk group.[74]

These studies demonstrated that fusion status was a better predictor of outcome than histology. Similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. Fusion status has now been incorporated into the risk stratification of patients in the current COG ARST1431 (NCT02567435) study for patients with intermediate-risk rhabdomyosarcoma, in subsequent COG trials, and in the new international EpSSG trial.[74] The authors underscored the probable value of treating fusion-negative patients whose tumors have alveolar histology with therapy that is stage appropriate for embryonal histology tumors.[75][Level of evidence C1]

Metastases at diagnosis

Children with metastatic disease at diagnosis have the worst prognosis.

The prognostic significance of metastatic disease is modified by the following:

• Tumor histology (embryonal rhabdomyosarcoma is more favorable than alveolar). Patients with localized alveolar histology and regional node disease have a similar prognosis as patients with a single site of metastatic disease, provided that the regional disease is treated with radiation therapy.[63]
• Age at diagnosis (<10 years for children with embryonal rhabdomyosarcoma).
• The site of primary disease. Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than patients with metastatic disease from other primary sites.[76]
• The number of metastatic sites.[77,78,79,80]

The COG performed a retrospective analysis of 179 patients who were diagnosed with rhabdomyosarcoma that was metastatic to the bone marrow. These patients were enrolled in one of four COG rhabdomyosarcoma clinical trials (D9802, D9803, ARST0431, and ARST08P1) between 1997 and 2013.[81] Patients were a median age of 14.8 years and 58% were male. Alveolar histology was the predominant type (76%), the extremity was the most common primary site (32%), and most patients had metastatic disease to additional sites (87%). The 3-year EFS rate was 9.4%, and the 5-year EFS rate was 8.2%. The 3-year OS rate was 26.1%, and the 5-year OS rate was 12.6%.

The COG performed a retrospective review of patients enrolled in high-risk protocols for rhabdomyosarcoma. FOXO1 fusion status correlated with clinical characteristics at diagnosis, including age, stage, histology, and extent of metastatic disease (Oberlin status). Among patients with metastatic disease, PAX::FOXO1 fusion status was not an independent predictor of outcome.[82][Level of evidence B1]

Lymph node involvement at diagnosis

Lymph node involvement at diagnosis is seen in about 23% of patients with rhabdomyosarcoma and is associated with an inferior prognosis.[62,83] Clinical and/or imaging evaluation is performed before treatment and preoperatively. These findings are incorporated into the initial staging and grouping of a patient with rhabdomyosarcoma. The updated TNM staging defines clinical node involvement as larger than 1 cm.[84]

Pathological assessment of nodal disease is determined by biopsy and incorporated in the Surgical/Pathologic Clinical Group classification. Core-needle or open biopsy of clinically enlarged nodes is appropriate to confirm the presence of disease. Approximately 25% of enlarged nodes will be pathologically negative. Suspicious nodes are sampled surgically with open biopsy, preferred to needle aspiration, although needle aspiration may occasionally be appropriate. Pathological evaluation of clinically uninvolved nodes is site specific. In COG studies, it is required for extremity sites and for boys older than 10 years with paratesticular primary tumors.[85] Given the poorer outcomes, pathological node evaluation is required for patients with fusion-positive disease in current European and North American clinical trials.

Data on the frequency of lymph node involvement in various sites are useful for making clinical decisions. For example, up to 40% of patients with rhabdomyosarcoma in genitourinary sites have lymph node involvement, while patients with certain head and neck sites have a much lower likelihood (<10%). Patients with nongenitourinary pelvic sites (e.g., anus/perineum) have an intermediate frequency of lymph node involvement.[86]

In the extremities and select truncal sites, sentinel lymph node evaluation is a more accurate form of diagnosis than random regional lymph node sampling. In clinically negative lymph nodes of the extremity or trunk, sentinel lymph node biopsy is the preferred form of node sampling by the COG. Technical considerations are obtained from surgical experts. Needle or open biopsy of clinically enlarged nodes is appropriate.[87,88,89,90] Lymph node removal does not improve outcome, and it is useful for staging but not treatment.

The EpSSG performed a retrospective analysis of 109 patients with rhabdomyosarcoma with extremity primary tumors distal to the elbow or knee who were treated in the EpSSG RMS-2005 (NCT00379457) trial (2005–2016).[91] Thirty-seven of 109 patients (34%) had lymph node metastases at diagnosis. Of the 37 patients, 19 (51%) had in-transit metastases (ITM), especially in lower extremity rhabdomyosarcoma. The 5-year EFS rates were 88.9% for patients with ITM, 21.4% for patients with proximal lymph node involvement, and 20% for combined proximal lymph node involvement and ITM (P = .01). The 5-year OS rates were 100% for patients with ITM, 25.2% for patients with proximal lymph node involvement, and 15% for patients with combined proximal lymph node involvement and ITM (P =. 003). The authors concluded that popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of ITM. The authors recommended biopsy of these nodes, especially for distal extremity rhabdomyosarcoma of the lower limb.

The EpSSG reported a retrospective analysis of 1,294 children with embryonal rhabdomyosarcoma enrolled in the RMS-2005 protocol.[92] Of these patients, 143 had nodal involvement (N1). Patients with N1 disease were older and presented with tumors of unfavorable size, invasiveness, site, and resectability. Unlike alveolar rhabdomyosarcoma, nodal involvement was more frequent in the head and neck area and rare in extremity sites. The 5-year EFS rate was 75.5%, and the OS rate was 86.3% for patients with N0 disease. The 5-year EFS rate was 65.2%, and the OS rate was 70.7% for patients with N1 disease. Nodal involvement and the result of surgery at diagnosis (Intergroup Rhabdomyosarcoma Study group) were independent prognostic factors on multivariate analysis. Investigators concluded that regional nodal involvement is an independent prognostic factor in patients with embryonal rhabdomyosarcoma; therefore, it is appropriate to include this population in the high-risk category.

Biological characteristics

For more information, see the Molecular Characteristics of Rhabdomyosarcoma section.

Response to therapy

It is unlikely that response to induction chemotherapy or best tumor response during therapy, assessed by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma. This finding was based on the IRSG, COG, and International Society of Pediatric Oncology (SIOP) studies that found no association.[93,94]; [95][Level of evidence C2]; [96][Level of evidence C1] However, an Italian study did find that patient response correlated with likelihood of survival.[54][Level of evidence C1] In patients with embryonal rhabdomyosarcoma who had metastases only in the lungs, the CWS assessed the relationship between complete response of the lung metastases at weeks 7 to 10 after chemotherapy and outcome in 53 patients.[97][Level of evidence C1] The 5-year survival rate was 68% for 26 complete responders at weeks 7 to 10 versus 36% for 27 patients who achieved complete responses at later time points (P = .004).

Other studies have investigated response to induction therapy, showing benefit to response. These data are somewhat flawed because therapy is usually tailored on the basis of response. Thus the situation is not as clear as the COG data suggest.[98,99,100,101,102,103]

Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) may be an early indicator of outcome [104] and is under investigation by several pediatric cooperative groups. A retrospective analysis of 107 patients from a single institution examined PET scans performed at baseline, after induction chemotherapy, and after local therapy.[104] Standardized uptake value measured at baseline predicted PFS and OS, but not local control. A negative scan after induction chemotherapy correlated with statistically significantly better PFS. A positive scan after local therapy predicted worse PFS, OS, and local control. The COG evaluated the relationship between complete metabolic response, as assessed by 18F-FDG PET imaging, and EFS in patients with intermediate- or high-risk rhabdomyosarcoma.[105][Level of evidence B4] The maximum standard uptake values (SUVmax) at study entry did not correlate with EFS for intermediate-risk (P = .32) or high-risk (P = .86) patients. Compared with patients who did not achieve a complete metabolic response, EFS was not superior for intermediate-risk patients who achieved a complete metabolic response at weeks 4 (P = .66) or 15 (P = .46), or for high-risk patients who achieved a complete metabolic response at weeks 6 (P = .75) or 19 (P = .28). Change in SUVmax at weeks 4 (P = .21) or 15 (P = .91) for intermediate-risk patients and at weeks 6 (P = .75) or 19 (P = .61) for high-risk patients did not correlate with EFS.

PET scans have been shown to be useful in understanding patterns of spread, particularly in patients with extremity disease.[106][Level of evidence C2]

Circulating tumor DNA (ctDNA) and RNA

A retrospective study of 99 children with rhabdomyosarcoma used reverse transcription–polymerase chain reaction to analyze an 11-gene panel in peripheral blood and bone marrow samples at the time of initial diagnosis.[107] The 5-year EFS rate was 35.5% (95% CI, 17.5%–53.5%) for the 33 patients who were RNA positive, compared with 88.0% (95% CI, 78.9%–97.2%) for the 66 patients who were RNA negative (P < .0001). The predictive power of the assay was maintained in a multivariate analysis, which included the usual clinical characteristics that correlate with prognosis such as the presence of metastatic disease. These investigators also studied the diagnostic potential of ctDNA in 57 patients enrolled in the EpSSG RMS-2005 (NCT00379457) study. ctDNA was detected using both shallow whole-genome sequencing (WGS) and cell-free reduced representation bisulfite sequencing (cfRRBS). Of the 25 samples tested, 21 were correctly classified as embryonal histology by cfRRBS. The presence of methylated RASSF1A correlated with a poor outcome.[108]

The COG analyzed ctDNA in 124 patients with newly diagnosed, intermediate-risk rhabdomyosarcoma from the COG biorepository, which included 75 patients with fusion-negative rhabdomyosarcoma and 49 patients with fusion-positive rhabdomyosarcoma.[109] Ultralow passage WGS was used to detect copy number alterations. Rhabdo-Seq, a new custom sequencing assay, was used to detect rearrangements and single-nucleotide variants (SNVs).

• The authors reported that ultralow passage WGS was a method that could detect ctDNA in all patients with fusion-negative rhabdomyosarcoma. ctDNA was detected in 13 of 75 serum samples (17%).
• However, the use of Rhabdo-Seq in fusion-negative rhabdomyosarcoma samples also identified SNVs, such as the L122R variant in the MYOD1 gene. This variant was previously associated with a poor prognosis.
• Identification of pathognomonic translocations between PAX3 or PAX7 and FOXO1 by Rhabdo-Seq was the best method for measuring ctDNA in fusion-positive rhabdomyosarcoma tumors. It detected ctDNA in 27 of 49 cases (55%).
• Patients with fusion-negative rhabdomyosarcoma with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (EFS rates, 33.3% vs. 68.9%; P = .0028; OS rates, 33.3% vs. 83.2%; P < .0001).
• Patients with fusion-positive rhabdomyosarcoma with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (EFS rates, 37% vs. 70%; P = .045; OS rates, 39.2% vs. 75%; P = .023).
• In a multivariate analysis, ctDNA was independently associated with poor prognoses in patients with fusion-negative rhabdomyosarcoma but not in the smaller cohort of patients with fusion-positive rhabdomyosarcoma.

References:

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
2. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.
4. Ognjanovic S, Linabery AM, Charbonneau B, et al.: Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer 115 (18): 4218-26, 2009.
5. WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
6. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
7. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993.
8. Casanova M, Meazza C, Favini F, et al.: Rhabdomyosarcoma of the extremities: a focus on tumors arising in the hand and foot. Pediatr Hematol Oncol 26 (5): 321-31, 2009 Jul-Aug.
9. Li FP, Fraumeni JF: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43 (6): 1365-73, 1969.
10. Diller L, Sexsmith E, Gottlieb A, et al.: Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 95 (4): 1606-11, 1995.
11. Trahair T, Andrews L, Cohn RJ: Recognition of Li Fraumeni syndrome at diagnosis of a locally advanced extremity rhabdomyosarcoma. Pediatr Blood Cancer 48 (3): 345-8, 2007.
12. Dehner LP, Jarzembowski JA, Hill DA: Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol 25 (4): 602-14, 2012.
13. Doros L, Yang J, Dehner L, et al.: DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatr Blood Cancer 59 (3): 558-60, 2012.
14. Ferrari A, Bisogno G, Macaluso A, et al.: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109 (7): 1406-12, 2007.
15. Crucis A, Richer W, Brugières L, et al.: Rhabdomyosarcomas in children with neurofibromatosis type I: A national historical cohort. Pediatr Blood Cancer 62 (10): 1733-8, 2015.
16. Gripp KW, Lin AE, Stabley DL, et al.: HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A 140 (1): 1-7, 2006.
17. Aoki Y, Niihori T, Kawame H, et al.: Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37 (10): 1038-40, 2005.
18. Gripp KW: Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137 (1): 72-7, 2005.
19. Kratz CP, Rapisuwon S, Reed H, et al.: Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet 157 (2): 83-9, 2011.
20. Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 32 (1): 38-43, 1999.
21. DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998.
22. Moschovi M, Touliatou V, Vassiliki T, et al.: Rhabdomyosarcoma in a patient with Noonan syndrome phenotype and review of the literature. J Pediatr Hematol Oncol 29 (5): 341-4, 2007.
23. Hasle H: Malignant diseases in Noonan syndrome and related disorders. Horm Res 72 (Suppl 2): 8-14, 2009.
24. Ognjanovic S, Carozza SE, Chow EJ, et al.: Birth characteristics and the risk of childhood rhabdomyosarcoma based on histological subtype. Br J Cancer 102 (1): 227-31, 2010.
25. Li H, Sisoudiya SD, Martin-Giacalone BA, et al.: Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Natl Cancer Inst 113 (7): 875-883, 2021.
26. Martin-Giacalone BA, Li H, Scheurer ME, et al.: Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From the Children's Oncology Group. JAMA Netw Open 7 (3): e244170, 2024.
27. Fair D, Maese L, Chi YY, et al.: TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report. Pediatr Blood Cancer : e30413, 2023.
28. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001.
29. Sung L, Anderson JR, Donaldson SS, et al.: Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Eur J Cancer 40 (12): 1878-85, 2004.
30. Malempati S, Rodeberg DA, Donaldson SS, et al.: Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. Cancer 117 (15): 3493-501, 2011.
31. Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009.
32. Streby KA, Ruymann FB, Whiteside S, et al.: Rhabdomyosarcoma in adolescents and young adults: A 25-year review at Nationwide Children's Hospital. J Adolesc Young Adult Oncol 1 (4): 164-167, 2012.
33. Van Gaal JC, Van Der Graaf WT, Rikhof B, et al.: The impact of age on outcome of embryonal and alveolar rhabdomyosarcoma patients. A multicenter study. Anticancer Res 32 (10): 4485-97, 2012.
34. Dumont SN, Araujo DM, Munsell MF, et al.: Management and outcome of 239 adolescent and adult rhabdomyosarcoma patients. Cancer Med 2 (4): 553-63, 2013.
35. Ragab AH, Heyn R, Tefft M, et al.: Infants younger than 1 year of age with rhabdomyosarcoma. Cancer 58 (12): 2606-10, 1986.
36. Ferrari A, Casanova M, Bisogno G, et al.: Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group. Cancer 97 (10): 2597-604, 2003.
37. Joshi D, Anderson JR, Paidas C, et al.: Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 42 (1): 64-73, 2004.
38. Bradley JA, Kayton ML, Chi YY, et al.: Treatment Approach and Outcomes in Infants With Localized Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Int J Radiat Oncol Biol Phys 103 (1): 19-27, 2019.
39. Sparber-Sauer M, Stegmaier S, Vokuhl C, et al.: Rhabdomyosarcoma diagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS). Pediatr Blood Cancer 66 (6): e27652, 2019.
40. Sparber-Sauer M, Matle M, Vokuhl C, et al.: Rhabdomyosarcoma of the female genitourinary tract: Primary and relapsed disease in infants and older children. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. Pediatr Blood Cancer 68 (4): e28889, 2021.
41. Slater O, Gains JE, Kelsey AM, et al.: Localised rhabdomyosarcoma in infants (<12 months) and young children (12-36 months of age) treated on the EpSSG RMS 2005 study. Eur J Cancer 160: 206-214, 2022.
42. Bisogno G, Minard-Colin V, Arush MB, et al.: Congenital rhabdomyosarcoma: A report from the European paediatric Soft tissue sarcoma Study Group. Pediatr Blood Cancer 69 (2): e29376, 2022.
43. Whittle S, Venkatramani R, Schönstein A, et al.: Congenital spindle cell rhabdomyosarcoma: An international cooperative analysis. Eur J Cancer 168: 56-64, 2022.
44. Gupta AA, Anderson JR, Pappo AS, et al.: Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer 118 (4): 1130-7, 2012.
45. Bisogno G, Compostella A, Ferrari A, et al.: Rhabdomyosarcoma in adolescents: a report from the AIEOP Soft Tissue Sarcoma Committee. Cancer 118 (3): 821-7, 2012.
46. Ferrari A, Chisholm JC, Jenney M, et al.: Adolescents and young adults with rhabdomyosarcoma treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) protocols: a cohort study. Lancet Child Adolesc Health 6 (8): 545-554, 2022.
47. Walterhouse DO, Pappo AS, Meza JL, et al.: Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 32 (31): 3547-52, 2014.
48. Pappo AS, Meza JL, Donaldson SS, et al.: Treatment of localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma: lessons learned from intergroup rhabdomyosarcoma studies III and IV. J Clin Oncol 21 (4): 638-45, 2003.
49. Merks JH, De Salvo GL, Bergeron C, et al.: Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups. Ann Oncol 25 (1): 231-6, 2014.
50. Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 2011.
51. Oberlin O, Rey A, Brown KL, et al.: Prognostic Factors for Outcome in Localized Extremity Rhabdomyosarcoma. Pooled Analysis from Four International Cooperative Groups. Pediatr Blood Cancer 62 (12): 2125-31, 2015.
52. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000.
53. Aye JM, Xue W, Palmer JD, et al.: Suboptimal outcome for patients with biliary rhabdomyosarcoma treated on low-risk clinical trials: A report from the Children's Oncology Group. Pediatr Blood Cancer 68 (4): e28914, 2021.
54. Ferrari A, Miceli R, Meazza C, et al.: Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol 28 (8): 1322-8, 2010.
55. Ferrari A, Miceli R, Meazza C, et al.: Soft tissue sarcomas of childhood and adolescence: the prognostic role of tumor size in relation to patient body size. J Clin Oncol 27 (3): 371-6, 2009.
56. Rodeberg DA, Stoner JA, Garcia-Henriquez N, et al.: Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. Cancer 117 (11): 2541-50, 2011.
57. Smith LM, Anderson JR, Qualman SJ, et al.: Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group. J Clin Oncol 19 (20): 4058-64, 2001.
58. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001.
59. Rodeberg DA, Wharam MD, Lyden ER, et al.: Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Int J Cancer 137 (1): 204-11, 2015.
60. Lautz TB, Chi YY, Li M, et al.: Benefit of delayed primary excision in rhabdomyosarcoma: A report from the Children's Oncology Group. Cancer 127 (2): 275-283, 2021.
61. Crist WM, Garnsey L, Beltangady MS, et al.: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8 (3): 443-52, 1990.
62. Meza JL, Anderson J, Pappo AS, et al.: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol 24 (24): 3844-51, 2006.
63. Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al.: Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 29 (10): 1304-11, 2011.
64. Wolden SL, Lyden ER, Arndt CA, et al.: Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 93 (5): 1071-6, 2015.
65. Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 113 (11): 3242-7, 2008.
66. Shenoy A, Alvarez E, Chi YY, et al.: The prognostic significance of anaplasia in childhood rhabdomyosarcoma: A report from the Children's Oncology Group. Eur J Cancer 143: 127-133, 2021.
67. Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 20 (11): 2672-9, 2002.
68. Williamson D, Missiaglia E, de Reyniès A, et al.: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28 (13): 2151-8, 2010.
69. Hibbitts E, Chi YY, Hawkins DS, et al.: Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children's Oncology Group. Cancer Med 8 (14): 6437-6448, 2019.
70. Skapek SX, Anderson J, Barr FG, et al.: PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer 60 (9): 1411-7, 2013.
71. Arnold MA, Anderson JR, Gastier-Foster JM, et al.: Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (4): 634-9, 2016.
72. Missiaglia E, Williamson D, Chisholm J, et al.: PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 30 (14): 1670-7, 2012.
73. Heske CM, Chi YY, Venkatramani R, et al.: Survival outcomes of patients with localized FOXO1 fusion-positive rhabdomyosarcoma treated on recent clinical trials: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 127 (6): 946-956, 2021.
74. De Salvo GL, Del Bianco P, Minard-Colin V, et al.: Reappraisal of prognostic factors used in the European Pediatric Soft Tissue Sarcoma Study Group RMS 2005 study for localized rhabdomyosarcoma to optimize risk stratification and generate a prognostic nomogram. Cancer 130 (13): 2351-2360, 2024.
75. Selfe J, Olmos D, Al-Saadi R, et al.: Impact of fusion gene status versus histology on risk-stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials. Pediatr Blood Cancer 64 (7): , 2017.
76. Koscielniak E, Rodary C, Flamant F, et al.: Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multi-center analysis. Med Pediatr Oncol 20 (3): 209-14, 1992.
77. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003.
78. Bisogno G, Ferrari A, Prete A, et al.: Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. Eur J Cancer 45 (17): 3035-41, 2009.
79. Dantonello TM, Winkler P, Boelling T, et al.: Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer 56 (5): 725-32, 2011.
80. Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008.
81. Schloemer NJ, Xue W, Qumseya A, et al.: Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies. Pediatr Blood Cancer 70 (12): e30701, 2023.
82. Rudzinski ER, Anderson JR, Chi YY, et al.: Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (12): , 2017.
83. Dasgupta R, Fuchs J, Rodeberg D: Rhabdomyosarcoma. Semin Pediatr Surg 25 (5): 276-283, 2016.
84. Crane JN, Xue W, Qumseya A, et al.: Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children's Oncology Group. Pediatr Blood Cancer 69 (6): e29644, 2022.
85. Walterhouse DO, Barkauskas DA, Hall D, et al.: Demographic and Treatment Variables Influencing Outcome for Localized Paratesticular Rhabdomyosarcoma: Results From a Pooled Analysis of North American and European Cooperative Groups. J Clin Oncol : JCO2018789388, 2018.
86. Lawrence W, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987.
87. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014.
88. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013.
89. Wright S, Armeson K, Hill EG, et al.: The role of sentinel lymph node biopsy in select sarcoma patients: a meta-analysis. Am J Surg 204 (4): 428-33, 2012.
90. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012.
91. Terwisscha van Scheltinga CEJ, Wijnen MHWA, Martelli H, et al.: In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study. Eur J Surg Oncol 48 (7): 1536-1542, 2022.
92. Ben-Arush M, Minard-Colin V, Scarzello G, et al.: Therapy and prognostic significance of regional lymph node involvement in embryonal rhabdomyosarcoma: a report from the European paediatric Soft tissue sarcoma Study Group. Eur J Cancer 172: 119-129, 2022.
93. Burke M, Anderson JR, Kao SC, et al.: Assessment of response to induction therapy and its influence on 5-year failure-free survival in group III rhabdomyosarcoma: the Intergroup Rhabdomyosarcoma Study-IV experience--a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 25 (31): 4909-13, 2007.
94. Lautz TB, Chi YY, Tian J, et al.: Relationship between tumor response at therapy completion and prognosis in patients with Group III rhabdomyosarcoma: A report from the Children's Oncology Group. Int J Cancer 147 (5): 1419-1426, 2020.
95. Rosenberg AR, Anderson JR, Lyden E, et al.: Early response as assessed by anatomic imaging does not predict failure-free survival among patients with Group III rhabdomyosarcoma: a report from the Children's Oncology Group. Eur J Cancer 50 (4): 816-23, 2014.
96. Vaarwerk B, van der Lee JH, Breunis WB, et al.: Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study. Cancer 124 (5): 1016-1024, 2018.
97. Sparber-Sauer M, von Kalle T, Seitz G, et al.: The prognostic value of early radiographic response in children and adolescents with embryonal rhabdomyosarcoma stage IV, metastases confined to the lungs: A report from the Cooperative Weichteilsarkom Studiengruppe (CWS). Pediatr Blood Cancer 64 (10): , 2017.
98. Koscielniak E, Harms D, Henze G, et al.: Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 17 (12): 3706-19, 1999.
99. Koscielniak E, Jürgens H, Winkler K, et al.: Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer 70 (10): 2557-67, 1992.
100. Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009.
101. Oberlin O, Rey A, Sanchez de Toledo J, et al.: Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol 30 (20): 2457-65, 2012.
102. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005.
103. Dantonello TM, Stark M, Timmermann B, et al.: Tumour volume reduction after neoadjuvant chemotherapy impacts outcome in localised embryonal rhabdomyosarcoma. Pediatr Blood Cancer 62 (1): 16-23, 2015.
104. Casey DL, Wexler LH, Fox JJ, et al.: Predicting outcome in patients with rhabdomyosarcoma: role of [(18)f]fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 90 (5): 1136-42, 2014.
105. Harrison DJ, Chi YY, Tian J, et al.: Metabolic response as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer Med 10 (3): 857-866, 2021.
106. La TH, Wolden SL, Rodeberg DA, et al.: Regional nodal involvement and patterns of spread along in-transit pathways in children with rhabdomyosarcoma of the extremity: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (4): 1151-7, 2011.
107. Lak NSM, Voormanns TL, Zappeij-Kannegieter L, et al.: Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease. Clin Cancer Res 27 (20): 5576-5585, 2021.
108. Lak NSM, van Zogchel LMJ, Zappeij-Kannegieter L, et al.: Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma. JCO Precis Oncol 7: e2200113, 2023.
109. Abbou S, Klega K, Tsuji J, et al.: Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 41 (13): 2382-2393, 2023.