Embryonal Rhabdomyosarcoma
        Botryoid and spindle cell subtypes
Alveolar Rhabdomyosarcoma
Pleomorphic (Anaplastic) Rhabdomyosarcoma
Chromosomal and Molecular Characteristics

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]

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 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]

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]

Pleomorphic rhabdomyosarcoma occurs predominantly in patients aged 30 to 50 years and is rarely seen in children. In children, the term "pleomorphic" has been replaced by the term "anaplastic."[4]

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation and which may be useful in the future for monitoring minimal residual disease during treatment.[5-8] Unique translocations between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 are characteristic of alveolar rhabdomyosarcoma.[5,9] 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.[5] Twenty-two percent of patients are negative for either PAX3 or PAX7 gene rearrangements. Patients with solid variant alveolar histology have a lower incidence of PAX-FKHR gene fusions compared to patients showing classical alveolar histology.[10] Among patients with alveolar histology and metastatic disease, those with PAX7 gene involvement and younger age may fare better.[11,12] In alveolar cases associated with the PAX3 gene, patients are older and have a higher incidence of invasive tumor (T2). Alveolar cases associated with the PAX7 gene appear to occur in patients at a younger age, and they may have longer event-free survival rates than those associated with PAX3 gene rearrangements.[11,13,14] Embryonal tumors, on the other hand, often show loss of specific genomic material from the short arm of chromosome 11.[9,15,16] The consistent loss of genomic material from the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, though no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma.[17] Gene expression arrays identify a cluster of genes that correlate with rhabdomyosarcomas which contain the PAX-FKHR translocation. Tumors with alveolar histology which lack the translocation have a gene expression profile more similar to embryonal rhabdomyosarcomas than alveolar rhabdomyosarcomas.[18] It is controversial whether translocation-negative rhabdomyosarcomas with some histologic features of alveolar rhabdomyosarcoma should be classified as embryonal based on gene expression profile rather than as alveolar by light microscopy findings.

References

1. Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006.  [PUBMED Abstract]
   
   
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. Kodet R, Newton WA Jr, Hamoudi AB, et al.: Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 17 (5): 443-53, 1993.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999.  [PUBMED Abstract]
   
   
10. Parham DM, Qualman SJ, Teot L, et al.: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol 31 (6): 895-901, 2007.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989.  [PUBMED Abstract]
    
    
17. Gordon T, McManus A, Anderson J, et al.: Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study. Med Pediatr Oncol 36 (2): 259-67, 2001.  [PUBMED Abstract]
    
    
18. 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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