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. 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. Both the botryoid and the spindle cell subtypes are associated with very favorable outcomes.
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.
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. In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplasia is preferred. 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.
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.
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. Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology. A retrospective analysis examined the correlation between immunohistochemistry and molecular pathology for fusion genes that are used in the diagnosis of alveolar rhabdomyosarcoma. 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. For congenital/infantile spindle cell rhabdomyosarcoma, recurrent NCOA2 gene rearrangements have been described. 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. 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.
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. 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.
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