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NCI/PDQ^® Health professionals: Childhood Rhabdomyosarcoma Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 17 de agosto del 2012

TABLE OF CONTENTS

• General Information
  • Incidence and Epidemiology
  • Prognostic Factors

• Cellular Classification
  • Embryonal Rhabdomyosarcoma
    • Botryoid and spindle cell subtypes
  • Alveolar Rhabdomyosarcoma
  • Pleomorphic (Anaplastic) Rhabdomyosarcoma
  • Molecular Classification

• Stage Information

• Treatment Option Overview

• Previously Untreated Childhood Rhabdomyosarcoma
  • Local Control Management: Surgery
  • Local Control Management: Radiation Therapy (RT)
  • Local Control Management with Surgery and RT by Primary Sites of Disease
    • Head and neck
    • Extremity sites
      • Regional and in-transit lymph nodes
    • Truncal sites
    • Genitourinary system
    • Unusual primary sites
    • Metastatic sites
  • Chemotherapy Treatment Options
    • Low-risk patients
    • Intermediate-risk patients
      • Treatment options under clinical evaluation
    • High-risk patients
      • Alternative Therapies
      • Treatment options under clinical evaluation
  • Current Clinical Trials

• Recurrent Childhood Rhabdomyosarcoma
  • Current Clinical Trials

• Changes to This Summary (08/17/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 1 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. 2 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. 1 Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For rhabdomyosarcoma, the 5-year survival rate has increased over the same time from 53% to 65% for children younger than 15 years and from 30% to 47% for adolescents aged 15 to 19 years. 1 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. 5

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. 5
• 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. 5
• Undifferentiated sarcoma: Compared with older patients, 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. 6

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. 9 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. 10 For patients with embryonal tumors, high birth weight and large size for gestational age are associated with an increased incidence of rhabdomyosarcoma. 11 Genetic conditions associated with rhabdomyosarcoma include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations), 12 13 14 neurofibromatosis type I, 15 Costello syndrome (with germline HRAS mutations), 16 17 18 Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated), 19 20 and Noonan syndrome. 21

Prognostic Factors

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 22 23 24 25 26 27 28; 29[Level of evidence: 3iiiA] as well as unique biological characteristics of rhabdomyosarcoma tumor cells. 30 It is unclear whether response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, as one study found an association and another study did not. 31 32[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 33 Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common for patients who have gross residual disease in unfavorable sites following initial surgery and those who have metastatic disease at diagnosis. 34

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 Intergroup Rhabdomyosarcoma Study Group (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. 6 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). 35
  • 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. 23 33 36 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. 23 37
  • 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 compared with 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. 38

• Site of origin: Primary sites with more favorable prognoses include the following: 7 8 39 40
  • 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. 7 Both tumor volume and maximum tumor diameter are associated with outcome. 32[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). 41 This was not confirmed by a Children's Oncology Group study of patients with intermediate-risk rhabdomyosarcoma. This was not confirmed by a Children's Oncology Group study of patients with intermediate-risk rhabdomyosarcoma. 42 This relationship requires prospective study to determine the therapeutic implications of the observation. 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. 24 43 44 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. 45

  Patients with otherwise localized disease but with proven regional lymph node involvement have a worse prognosis than do patients without regional nodal involvement. 27 28

• Resectability: The extent of disease following the primary surgical procedure (i.e., the Surgical-pathologic Group, formerly called the Clinical Group) is also correlated with outcome. 7 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 following surgery (Group II). 7 22 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%. 46
• 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). 39 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. 47 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. 7

  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%). 48

  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). = .081). 49

• Biological characteristics: Refer to the Molecular Classification section of this summary for more information.

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 compared with children. 35

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.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997. [PUBMED Abstract]
3. Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995. [PUBMED Abstract]
4. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online [PUBMED Abstract]
5. 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. [PUBMED Abstract]
6. 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. [PUBMED Abstract]
7. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PUBMED Abstract]
8. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993. [PUBMED Abstract]
9. 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. [PUBMED Abstract]
10. Gurney JG, Young JL Jr, Roffers SD, et al.: Soft tissue sarcomas. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 111-123. Also available online. [PUBMED Abstract]
11. 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. [PUBMED Abstract]
12. Li FP, Fraumeni JF Jr: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43 (6): 1365-73, 1969. [PUBMED Abstract]
13. 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. [PUBMED Abstract]
14. 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. [PUBMED Abstract]
15. 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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
18. Gripp KW: Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137 (1): 72-7, 2005. [PUBMED Abstract]
19. Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 32 (1): 38-43, 1999. [PUBMED Abstract]
20. 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. [PUBMED Abstract]
21. 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. [PUBMED Abstract]
22. 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. [PUBMED Abstract]
23. 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. [PUBMED Abstract]
24. 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. [PUBMED Abstract]
25. La Quaglia MP, Heller G, Ghavimi F, et al.: The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 73 (1): 109-17, 1994. [PUBMED Abstract]
26. Punyko JA, Mertens AC, Baker KS, et al.: Long-term survival probabilities for childhood rhabdomyosarcoma. A population-based evaluation. Cancer 103 (7): 1475-83, 2005. [PUBMED Abstract]
27. Lawrence W Jr, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987. [PUBMED Abstract]
28. Mandell L, Ghavimi F, LaQuaglia M, et al.: Prognostic significance of regional lymph node involvement in childhood extremity rhabdomyosarcoma. Med Pediatr Oncol 18 (6): 466-71, 1990. [PUBMED Abstract]
29. Dantonello TM, Int-Veen C, Winkler P, et al.: Initial patient characteristics can predict pattern and risk of relapse in localized rhabdomyosarcoma. J Clin Oncol 26 (3): 406-13, 2008. [PUBMED Abstract]
30. 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. [PUBMED Abstract]
31. 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. [PUBMED Abstract]
32. 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. [PUBMED Abstract]
33. 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. [PUBMED Abstract]
34. 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. [PUBMED Abstract]
35. 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. [PUBMED Abstract]
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. [PUBMED Abstract]
37. 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. [PUBMED Abstract]
38. 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. [PUBMED Abstract]
39. 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. [PUBMED Abstract]
40. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000. [PUBMED Abstract]
41. 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. [PUBMED Abstract]
42. 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 : , 2010. [PUBMED Abstract]
43. 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. [PUBMED Abstract]
44. 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. [PUBMED Abstract]
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46. 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. [PUBMED Abstract]
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48. 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. [PUBMED Abstract]
49. 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. [PUBMED Abstract]

Cellular Classification

Rhabdomyosarcoma can be divided into several histologic subsets: embryonal rhabdomyosarcoma, which has embryonal, botryoid, and spindle cell subtypes; alveolar rhabdomyosarcoma; and pleomorphic rhabdomyosarcoma. 1 2

Embryonal Rhabdomyosarcoma

The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60% to 70% of rhabdomyosarcomas of childhood. 1 Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site.

Botryoid and spindle cell subtypes

Botryoid tumors represent about 10% of all rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract. The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site. 3 Both the botryoid and the spindle cell subtypes are associated with very favorable outcomes. 2

Alveolar Rhabdomyosarcoma

Approximately 20% of children with rhabdomyosarcoma have the alveolar subtype. An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region. 1

For current trials developed by the Soft Tissue Sarcoma Committee of the Children's Oncology Group, to be designated as alveolar, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal. In some earlier studies (the D series, 19972005), any alveolar focus was sufficient, but that criterion was later abandoned.

Pleomorphic (Anaplastic) Rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is rarely seen in children. 4 In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplasia is preferred. 5 In a retrospective review of 546 pediatric patients, the presence of anaplasia was only associated in univariate analysis with inferior clinical outcome in patients with intermediate-risk rhabdomyosarcoma. 6

Molecular Classification

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning therapy and monitoring residual disease during treatment. 7 8 9 10 11

• Alveolar histology: Unique translocations between the FOXO1 (previously called FKHR) gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)) are found in 70% to 80% of patients with alveolar histology tumors. 7 12 Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases. 7 Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology. 13

  Alveolar cases associated with the PAX7 gene, with or without metastases, appear to occur in patients at a younger age, and may be associated with longer event-free survival (EFS) rates than those associated with gene, with or without metastases, appear to occur in patients at a younger age, and may be associated with longer event-free survival (EFS) rates than those associated with PAX3 gene rearrangements. gene rearrangements. 14 15 16 17 Alveolar cases associated with the Alveolar cases associated with the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation. gene translocation. 11 13

• Embryonal histology: Embryonal tumors often show loss of specific genomic material from the short arm of chromosome 11. 12 18 19 The consistent loss of genomic material at the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, although no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma. 20

These findings highlight the important differences between embryonal and alveolar tumors. There are data that alveolar tumors carrying either a t(1;13) or a t(2;13) translocation (translocation-positive) are biologically and clinically different from alveolar tumors that do not have a translocation (translocation-negative) and from embryonal tumors. 11 21 22 23 In a study of Intergroup Rhabdomyosarcoma Study Group (IRSG) cases, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases and was similar to that seen in patients with embryonal rhabdomyosarcoma, suggesting that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma. 22 However, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were PAX-FOXO1positive compared with those who were translocation-negative. 24

A study suggests that metagene expression analyses can classify patients with rhabdomyosarcoma into the three distinct risk groups and may be particularly helpful in identifying intermediate-risk patients with poor-risk features. Further studies are needed to confirm these findings. 21

References:

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4. 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. [PUBMED Abstract]
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6. 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. [PUBMED Abstract]
7. Barr FG, Smith LM, Lynch JC, et al.: Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group. J Mol Diagn 8 (2): 202-8, 2006. [PUBMED Abstract]
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Stage Information

Before a biopsy of a suspected tumor mass is performed, imaging studies of the mass and baseline laboratory studies should be obtained. After the diagnosis of rhabdomyosarcoma has been made, an extensive evaluation to determine the extent of the disease should be done prior to instituting therapy. This evaluation should include a chest x-ray, computed tomography (CT) scan of the chest, bilateral bone marrow aspirates and biopsies, bone scan, magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors only), and CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).

A CT or MRI scan of regional lymph nodes should be considered. Abnormal-appearing lymph nodes should be biopsied when possible. One study has demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies may alter the treatment plan. 1 Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities. 2 3 4 However, the efficacy of these two procedures for identifying involved lymph nodes or other sites is currently under investigation, and these procedures are not required by current treatment protocols.

Terms used in this summary section are defined below in Table 1.

Staging of rhabdomyosarcoma is relatively complex. The process includes the following steps:

1. Assigning a Stage: Determined by primary site, tumor size (widest diameter), and presence or absence of regional lymph node and/or distant metastases.
2. Assigning a local tumor Group: Determined by status postsurgical resection/biopsy, with pathologic assessment of the tumor margin and of lymph node disease.
3. Assigning a Risk Group: Determined by Stage, Group, and histology.

As noted previously, prognosis for children with rhabdomyosarcoma depends predominantly on the primary site, tumor size, Group, and histologic subtype. Favorable prognostic groups were identified in previous Intergroup Rhabdomyosarcoma Study Group (IRSG) studies, and treatment plans were designed on the basis of assignment of patients to different treatment groups according to prognosis. Several years ago, the IRSG merged with the National Wilms Tumor Study Group and two large cooperative pediatric cancer treatment groups to form the Children's Oncology Group (COG). New protocols for children with soft tissue sarcoma are developed by the Soft Tissue Sarcoma Committee of the COG (COG-STS).

Current COG-STS protocols for rhabdomyosarcoma use the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 2 below. 5 6

The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on the Surgical-pathologic Group system. In this system, Groups are defined by the extent of disease and by the completeness or extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 3 below. 7 8

After patients