Ewing Sarcoma: A Comprehensive Review of Its Classification, Diagnosis, and Emerging Treatments

Ewing sarcoma comprises a group of highly aggressive malignant neoplasms that predominantly affect children, adolescents, and young adults. It is classified among small round cell tumors and is cytogenetically characterized by specific chromosomal translocations, the most common being t(11;22) (q24;q12), which results in the fusion of the EWSR1 gene with members of the ETS transcription factor family, primarily FLI1. This genetic alteration plays a pivotal role not only in malignant transformation but also serves as a key diagnostic biomarker. Epidemiologically, Ewing sarcoma represents the second most frequent primary bone tumor in the pediatric population, with a clear predominance in males and individuals of Caucasian descent. Clinically, it typically presents as localized bone pain, often accompanied by swelling or a palpable mass, and in some cases, systemic symptoms. The most common locations include the long bones of the lower limbs and the pelvis. Diagnosis requires a multidisciplinary approach encompassing advanced radiological studies (magnetic resonance imaging, computed tomography), bone scintigraphy, and histological confirmation through biopsy, supported by immunohistochemical techniques (such as CD99 expression), and molecular analyses for the detection of gene fusions. The standard treatment is based on a combination of intensive systemic chemotherapy, radical surgery, and, in some cases, radiotherapy. Multicenter clinical trials, such as the Euro-Ewing 99 protocol, have optimized therapeutic strategies, improving survival rates in localized disease (up to 70% - 75%), and reducing the long-term adverse effects. Nevertheless, the prognosis remains poor in patients with metastatic or recurrent disease, prompting the development of targeted therapies, immunotherapies (such as IGF-1R inhibitors or T cell-based strategies), and personalized approaches guided by molecular profiles. This article presents an up-to-date and comprehensive review of Ewing sarcoma, focusing on its biological classification, clinical manifestations, diagnostic methods, current therapeutic options, and emerging advances in translational research, with an emphasis on the need to individualize clinical management, and explore new therapeutic targets to improve outcomes in high-risk subgroups.