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Childhood Rhabdomyosarcoma Treatment (PDQ®)

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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, 1997–2005), 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.[7-11]

  • Alveolar histology: About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 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)).[7,12,13] Other rare fusions include PAX3-NCOA1 and PAX3-INO80D.[14] 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.[15] A retrospective analysis examined the correlation between immunohistochemistry and molecular pathology for fusion genes that are used in the diagnosis of alveolar rhabdomyosarcoma.[16] An algorithm that included four immunohistochemistry markers (myogenin, AP-2-beta, NOS-1, and HMGA2) had a 96% sensitivity of predicting fusion positivity, with a 91% to 92% specificity. The authors suggest that this could help characterize cases in which molecular pathology is unavailable.

    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 PAX3 gene rearrangements.[17-22] 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 PAX gene translocation.[11,15] In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[14,23] BCOR and PIK3CA mutations and amplification of MYCN, MIR17HG, and CDK4 have also been described.

  • Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[13,24,25] Embryonal tumors have a higher background mutation rate and higher single-nucleotide variant rate than do alveolar tumors, and the number of somatic mutations increases with older age at diagnosis.[14,23] Genes with recurring mutations include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-third of cases. Other genes with recurring mutations include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 10% of cases.[14,23]
  • Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the WHO Classification of Tumours of Soft Tissue and Bone.[26] For congenital/infantile spindle cell rhabdomyosarcoma, recurrent NCOA2 gene rearrangements have been described.[27] In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 mutation (p.L122R) has been observed in a large proportion of patients.[28-30] The presence of the MYOD1 mutation is associated with an increased risk of treatment failure.[28,29]

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.[11,31-34] 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.[32] However, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were PAX-FOXO1–positive compared with those who were translocation-negative.[35]

One 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.[31] In another study, gene expression signature did not appear to add additional prognostic information beyond that available from the contribution of the PAX3/FOX01 fusion status.[21]


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  2. Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer 76 (6): 1073-85, 1995. [PUBMED Abstract]
  3. Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995. [PUBMED Abstract]
  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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  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]
  8. Kelly KM, Womer RB, Barr FG: Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 78 (6): 1320-7, 1996. [PUBMED Abstract]
  9. Edwards RH, Chatten J, Xiong QB, et al.: Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol 6 (2): 91-7, 1997. [PUBMED Abstract]
  10. Sartori F, Alaggio R, Zanazzo G, et al.: Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers. Cancer 106 (8): 1766-75, 2006. [PUBMED Abstract]
  11. Davicioni E, Anderson MJ, Finckenstein FG, et al.: Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol 174 (2): 550-64, 2009. [PUBMED Abstract]
  12. Dumont SN, Lazar AJ, Bridge JA, et al.: PAX3/7-FOXO1 fusion status in older rhabdomyosarcoma patient population by fluorescent in situ hybridization. J Cancer Res Clin Oncol 138 (2): 213-20, 2012. [PUBMED Abstract]
  13. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999. [PUBMED Abstract]
  14. Shern JF, Chen L, Chmielecki J, et al.: Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 4 (2): 216-31, 2014. [PUBMED Abstract]
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  16. Rudzinski ER, Anderson JR, Lyden ER, et al.: Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group. Am J Surg Pathol 38 (5): 654-9, 2014. [PUBMED Abstract]
  17. 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]
  18. Krsková L, Mrhalová M, Sumerauer D, et al.: Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement. Virchows Arch 448 (4): 449-58, 2006. [PUBMED Abstract]
  19. Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997. [PUBMED Abstract]
  20. Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002. [PUBMED Abstract]
  21. 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. [PUBMED Abstract]
  22. Duan F, Smith LM, Gustafson DM, et al.: Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer 51 (7): 662-74, 2012. [PUBMED Abstract]
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  24. Koufos A, Hansen MF, Copeland NG, et al.: Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316 (6026): 330-4, 1985 Jul 25-31. [PUBMED Abstract]
  25. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989. [PUBMED Abstract]
  26. Nascimento AF, Barr FG, Fletcher CD, et al., eds.: Spindle cell/sclerosing rhabdomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013, pp 134-5.
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  28. Kohsaka S, Shukla N, Ameur N, et al.: A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46 (6): 595-600, 2014. [PUBMED Abstract]
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  33. Davicioni E, Finckenstein FG, Shahbazian V, et al.: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 66 (14): 6936-46, 2006. [PUBMED Abstract]
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  35. Stegmaier S, Poremba C, Schaefer KL, et al.: Prognostic value of PAX-FKHR fusion status in alveolar rhabdomyosarcoma: a report from the cooperative soft tissue sarcoma study group (CWS). Pediatr Blood Cancer 57 (3): 406-14, 2011. [PUBMED Abstract]
  • Updated: April 9, 2015