Embryonal rhabdomyosarcoma is a sarcoma type that shows spindle cell cytomorphology and skeletal muscle differentiation. Botryoid rhabdomyosarcoma and anaplastic rhabdomyosarcoma are specific embryonal rhabdomyosarcoma subtypes with distinctive clinicopathologic features. 

Embryonal rhabdomyosarcoma is the most common sarcoma in children, and it shows a slight male predominance in general.¹ Botryoid rhabdomyosarcoma shows a striking female predominance and a strong predilection for vaginal mucosa. 

Embryonal rhabdomyosarcoma occurs most commonly in the head and neck and genitourinary tract.² It usually presents as an enlarging, painless mass, although some cases present due to mass effect on adjacent structures. The botryoid subtype (see below) most often presents as a polypoid multinodular mass extruding from the vaginal introitus. Anaplastic rhabdomyosarcoma is associated with Li-Fraumeni syndrome in at least 10% of cases.^3,4

Embryonal rhabdomyosarcoma shows atypical spindle cells with sheet-like, variably solid growth and myxoid stroma. Some examples exhibit conspicuous, strap-like rhabdomyoblasts. Botryoid rhabdomyosarcoma shows characteristic condensation of neoplastic cells immediately deep to epithelial surfaces in a so-called “cambium layer”. Anaplastic rhabdomyosarcoma shows either focal or diffuse anaplasia, characterized by pleomorphic neoplastic cells with bizarre nuclear atypia.

Neoplastic cells express desmin, and, consistent with a somewhat mature differentiation state, they generally express myo-D1 more diffusely than myogenin.^5,6 

Embryonal rhabdomyosarcoma is a malignancy with a 5-year event-free survival of about 75%.⁷ The most important prognostic factor is stage at presentation, and young age is associated with better outcomes.⁷ The botryoid subtype has a favorable prognosis, with up to 95% of patients achieving cure;⁸ however, botryoid rhabdomyosarcoma does tend to present at lower stage, and its prognosis is not significantly better than that of stage-matched conventional embryonal rhabdomyosarcoma.⁹ Data are mixed regarding the prognosis of anaplastic rhabdomyosarcoma; while univariate analysis shows anaplastic morphology to be a poor prognostic factor, this finding has not borne out on multivariate analysis.^10,11 Embryonal rhabdomyosarcoma shows similar genetics and clinical outcomes as fusion-negative alveolar rhabdomyosarcoma, and so some clinical studies combine these groups into a so-called “fusion-negative rhabdomyosarcoma” category.^1,12

• There are no specific or recurrent gene fusions in embryonal rhabdomyosarcoma.¹³

• Sporadic embryonal rhabdomyosarcoma shows aneuploidy in most cases.¹ The most common chromosomal alteration is polysomy of chromosome 8.¹⁴ Other recurrent alterations include gains in chromosomes 2, 7, 11, 12, 13, 17, 18, 19, and 20.^13-15 Monosomy 9, 10, 14, 15, and 16 are also recurrent, as is loss of 1p.^13,15,16

• RAS pathway alterations are present in around 50% of embryonal rhabdomyosarcoma.¹⁷ These include mutations in NRAS, KRAS, and HRAS, the latter of which are sometimes associated with germline HRAS mutations (Costello syndrome), as well as other RASopathies including Noonan syndrome and type I neurofibromatosis.^18-20 HRAS and KRAS mutations have a higher prevalence in very young children, while NRAS mutations have a higher prevalence in adolescent patients.¹⁷

• TP53 mutations are present in up to 15% of embryonal rhabdomyosarcoma and are associated with a worse prognosis.¹⁷ At least 10% of embryonal rhabdomyosarcoma harboring TP53 mutations are associated with Li-Fraumeni syndrome, so germline testing should be considered in such cases.^3,4

• BCOR is altered in 7-15% of embryonal rhabdomyosarcoma.^13,17

• Embryonal rhabdomyosarcoma harbors DICER1 mutations in 2% of reported cases in general, and these DICER1-mutant tumors show a predilection for the female genital tract.¹⁷ DICER1-mutant tumors also often show cartilaginous differentiation, an otherwise unusual feature in conventional embryonal rhabdomyosarcoma, and rhabdomyoblastic differentiation is commonly seen in DICER1-altered sarcomas in general.²¹ Whether DICER1-mutant embryonal rhabdomyosarcoma should be co-classified with other embryonal rhabdomyosarcoma or specifically as their own subclass remains uncertain.²²