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Histologically, embryonal rhabdomyosarcoma commonly presents as alternating loose and dense patches of cells. The heterogenous structure resembles striated muscle at various embryonal developmental stages.

Embryonal rhabdomyosarcoma is generally associated with better prognosis than alveolar rhabdomyosarcoma, which has a more aggressive and metastatic nature that can be attributed to its PAX3–FOXO1 or PAX7–FOXO1 gene fusions.

Diagnosis
Rhabdomyosarcoma is diagnosed through the presence of embryonic myogenesis, which can be identified through morphological examination as well as assays containing myogenic markers. Immunohistochemical assays use protein expression to determine the fusion status of the growth, differentiating fusion-negative embryonal rhabdomyosarcoma from fusion-positive alveolar rhabdomyosarcoma. Fusion-status is determined through the expression of certain proteins, such as myogenin, although the assay panel used for diagnosis depends on the tumor morphology.

The Horn-Enterline classification uses morphologic characteristics to divide rhabdomyosarcoma into the embryonal, alveolar, botryoid, and pleomorphic subtypes. However, due to recent advancements in molecular genetics, the genetic and epigenetic factors contributing to these morphological differences have been more closely examined. As a result, the World Health Organization currently takes into account both molecular genetics and morphology to classify rhabdomyosarcoma into the embryonal, alveolar, spindle cell/sclerosing, and pleomorphic subtypes.

The identification of rhabdomyoblasts is key to diagnosing rhabdomyosarcoma. This is done using immunohistochemistry to test for the expression of immunomarkers, or certain proteins that indicate muscle differentiation. These immunomarkers include desmin, muscle-specific actin, Myogenin, and MyoD1, the latter two being transcription factors that are involved in muscle differentiation. The performance of molecular genetic tests as well as matching the genotypic result to the clinical presentation are necessary to confirm the diagnosis of of rhabdomyosarcoma as well as identify a subtype. Risk stratification, prognosis, and intensity of treatment are all more correlated with fusion-status rather than morphological subtype. Due to the lack of biological differences between ERMS and fusion-negative, histologic ARMS, the World Health Organization recommends the consideration of fusion-negative ARMS as a "primitive form of ERMS".

Genomic patterns associated with ERMS include the gains in chromosomes 8, 2, 11, 12, 13, and/or 20 and losses in chromosomes 10 and 15. Another common genomic alteration is loss of heterozygosity at chromosome 11p. Approximately 10% of ERMS cases include a loss of function mutation at TP53, which results in anaplasia. An international study of more than 600 people with RMS showed worst outcomes in cases with anaplasia, regardless of fusion-status. Approximately 50% of ERMS is associated with RAS mutations, with NRAS mutations more common in adolescent cases and HRAS and KRAS mutations occurring in 70% of infant cases.

The botryoid variant of ERMS occurs in mucosal-lined organs such as the common bile duct, bladder, and vagina. The etymology for this variant name comes from "grape clusters", referring to the gross appearance of of grape-like masses. The defining feature used for diagnosing the botryoid variant is the histologically visible cambium layer, but cases in which this layer is narrow or absent may result in misdiagnosis.

Genetic conditions such as Gorlin syndrome, neurofibromatosis type 1, and Beckwith-Wiedemann syndrome have been shown to predispose individuals to embryonal rhabdomyosarcoma. Risk Factors associated with possible increased Embryonal Rhabdomyosarcoma include cigarette smoking, older age of mother, x-ray exposure, and maternal drug use.