Embryonal rhabdomyosarcoma (EMRS) is a rare histological form of cancer in the connective tissue wherein the mesenchymally-derived malignant cells resemble the primitive developing skeletal muscle of the embryo. It is the most common soft tissue sarcoma occurring in children. Embryonal rhabdomyosarcoma is also known as PAX-fusion negative or Fusion-Negative rhabdomyosarcoma, as tumors of this subtype are unified by their lack of a PAX3-FOXO1 fusion oncogene (or other PAX fusions seen in alveolar rhabdomyosarcoma). Fusion status refers to the presence or absence of a fusion gene, which is a gene formed from joining two different genes together through DNA rearrangements. These types of tumors are classified as embryonal rhabdomyosarcoma "because of their remarkable resemblance to developing embryonic and fetal skeletal muscle." Classification
Embryonal rhabdomyosarcoma is the more common of the two major sub-types of rhabdomyosarcoma. ERMS accounts for 60% to 70% of rhabdomyosarcoma, the other being alveolar rhabdomyosarcoma (ARMS), also known as PAX-fusion positive or Fusion Positive rhabdomyosarcoma. Most often, ERMS is found in children during ages 0 to 5 years old, however ERMS can develop throughout any stage of life. Embryonal rhabdomyosarcoma can be further divided into three  subcategories: the botryoid, spindle cell, and not-otherwise-specified (NOS). These two subtypes of rhabdomyosarcoma, ERMS and ARMS, also are caused by different genetic mutation pathways.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.
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. Embryonal rhabdomyosarcoma is commonly driven by a mutation in the RAS family of proto-oncogenes, creating a powerful signal which is now known to promote tumor growth by preventing muscle lineage progression by blocking expression of the transcription factor myogenin. Inhibition of this signaling pathway with a cancer medication, trametinib, has been recently shown to overcome this differentiation block and reduce tumor progression in animal models of embryonal rhabdomyosarcoma.Tumor suppressor gene mutations, such as TP53 mutations, were shown in about 13% in the mutations and MYOD1 mutations were seen in about 3% of the mutations. Tumor suppressors signal the cell to stop the cell cycle and start apoptosis, known as programmed cell death, when the cell senses damage or irregular cell cycle growth patterns. Approximately 10% of ERMS cases include a loss of function mutation at TP53, which results in anaplasia, poor cellular differentiation that can be identified through nuclei that are larger and darker-colored than normal. An international study of more than 600 people with RMS showed worst outcomes in cases with anaplasia, regardless of fusion-status. Predisposing Conditions
Genetic conditions such as Gorlin syndrome, neurofibromatosis type 1, Beckwith-Wiedemann syndrome, Li-Fraumeni syndrome, Noonan syndrome, Costello syndrome, and DICER1 syndrome have been shown to predispose individuals to embryonal rhabdomyosarcoma. Risk factors associated with embryonal rhabdomyosarcoma include cigarette smoking, older age of birth parent, x-ray exposure, and maternal drug use.