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Ewing sarcoma

Ewing sarcoma is a rare and aggressive type of cancer that forms in the or the soft tissues surrounding them, primarily affecting children, adolescents, and young adults. It is the second most common type of primary cancer in children and adolescents after . It typically begins as a small, round cell tumor and is part of the Ewing family of tumors, which share similar genetic and histological features. Ewing sarcoma accounts for approximately 1% of all childhood cancers, with around 200 new cases diagnosed annually in children and teenagers . The disease is most common in individuals under 20 years of age, with a peak incidence between 15 and 20 years, and it is exceedingly rare in adults over 40. It predominantly occurs in people of descent and is less frequent in those of or East Asian ancestry. The most common sites are the bones of the legs (such as the or ), pelvis, and , though extraosseous () presentations also occur. The primary symptoms of Ewing sarcoma include persistent pain in the affected area, which may worsen at night or with activity, and noticeable swelling or a lump near the tumor site. Other signs can involve bone fractures from minimal , fever, , and unexplained weight loss, particularly if the cancer has spread. These symptoms often mimic other conditions like infections or injuries, leading to potential delays in diagnosis. The exact cause of Ewing sarcoma remains unknown, but it is driven by specific genetic abnormalities, most commonly a between chromosomes 11 and 22—t(11;22)—that fuses the EWSR1 gene with the FLI1 gene, resulting in uncontrolled . These mutations are and not typically inherited, with no clear environmental triggers identified. Risk factors are limited, but the higher prevalence in certain ethnic groups suggests possible genetic predispositions. Diagnosis involves imaging studies such as X-rays, MRI, or scans to locate the tumor, followed by a to confirm the presence of characteristic small round blue cells and for the translocation. assesses spread, often using scans or bone marrow biopsies, as the cancer frequently metastasizes to the lungs, other bones, or at . is multimodal and typically includes neoadjuvant to shrink the tumor, followed by surgery to remove it if possible, or for inoperable cases, with additional to eliminate residual disease. varies by stage, with five-year rates around 81% for localized disease but lower (around 41%) for metastatic cases.

Overview

Definition and classification

Ewing sarcoma is a rare and aggressive thought to arise from primitive neuroectodermal or mesenchymal progenitor cells, primarily involving bones and soft tissues, and is characterized by its potential for rapid . It is the second most common type of primary bone sarcoma in children and adolescents after . It accounts for approximately 1-3% of all childhood cancers and is typically diagnosed in individuals under 20 years of age, with a peak incidence between 10 and 20 years. As a member of the Ewing family of tumors (EFT), Ewing sarcoma encompasses subtypes such as Ewing sarcoma of bone (ESB), which originates within the bone, and extraosseous Ewing sarcoma (EES), which develops in soft tissues adjacent to bones. These tumors share defining genetic features, including the t(11;22), which distinguishes them from other sarcomas (detailed in the genetics section). Histologically, Ewing sarcoma presents as a small round blue cell tumor composed of uniform, densely packed cells with a high , scant often rich in , and occasional formations such as Homer-Wright rosettes. These features aid in differentiating it from similar small round cell tumors like or . Staging of Ewing sarcoma, particularly for bone involvement, commonly employs the Musculoskeletal Tumor Society (MSTS) system, also known as the Enneking staging system, which assesses tumor grade (low or high), site (intracompartmental or extracompartmental), and the presence of to classify the disease into stages I-III. This system guides surgical and therapeutic planning by evaluating local extent and systemic spread.

Epidemiology

Ewing sarcoma is a rare , with a global incidence of approximately 2-3 cases per million children and adolescents annually. In the United States, the incidence rate is about 2.9 cases per million individuals from birth to age 20 years, translating to roughly 200-250 new diagnoses each year among children and teenagers. Higher rates are observed in and compared to other regions, with some European countries reporting up to 3-4 cases per million in the 10-19 age group, while overall international estimates remain below 2 cases per million children worldwide. The disease predominantly affects children and young adults, with the peak incidence occurring between ages 10 and 14 years, accounting for about half of all cases. It is uncommon in children under 5 years and rare in adults over 30, comprising less than 10% of diagnoses in those older than 20. Males are affected more frequently than females, with a ratio of approximately 1.6:1. Geographic and ethnic variations are notable, with higher incidence among individuals of descent (1.55 cases per million in the ) compared to lower rates in (0.2 per million) and Asian (0.8 per million) populations. These disparities suggest potential genetic or environmental influences tied to ancestry, though the exact mechanisms remain unclear. In regions like and , the incidence is substantially lower, often approaching zero in some registries. No strong environmental risk factors have been established, though rare associations with prior have been reported in a small subset of cases. Genetic predisposition may play a role, with inherited variants in DNA damage repair genes, such as those involved in , increasing susceptibility in some families. Incidence trends have shown increases in many regions from 1988 to 2012, with variations by geography and age group.

Genetics and pathogenesis

Genetic abnormalities

Ewing sarcoma is characterized by a primary genetic event involving the t(11;22)(q24;q12), which occurs in approximately 85-90% of cases and results in the fusion of the EWSR1 gene on chromosome 22q12 with the FLI1 gene on chromosome 11q24. This translocation was first identified in 1992 by Delattre et al., who described the resulting EWSR1-FLI1 fusion as generating an aberrant that drives oncogenesis. Variant translocations account for the remaining cases, with the second most common being t(21;22)(q22;q12), involving of EWSR1 with ERG on chromosome 21q22, observed in about 5-10% of tumors. Rarer fusions include EWSR1-ETV1 (t(7;22)) and EWSR1-FEV (t(17;22)), each present in less than 1% of cases and also resulting in chimeric transcription factors similar to the primary . In addition to the defining translocations, Ewing sarcoma tumors often exhibit secondary genetic alterations, including deletions on chromosomes 1p and 16q, as well as gains on 8q and 12q, which are detected in a subset of cases and may contribute to tumor progression. in TP53 and STAG2 occur in approximately 5-15% and 15-20% of tumors, respectively, particularly in those with advanced disease at diagnosis, and are associated with inferior . Detection of these genetic abnormalities plays a key role in confirming the of Ewing sarcoma, with (FISH) using break-apart probes for EWSR1 being a sensitive method to identify rearrangements regardless of the partner. (RT-PCR) is also widely used to detect specific transcripts, such as EWSR1-FLI1 or EWSR1-ERG, offering high specificity on fresh or formalin-fixed tissue. These molecular tests are essential for distinguishing Ewing sarcoma from other small round cell tumors. The EWSR1-FLI1 functions as an aberrant , which underlies the molecular mechanisms of explored further in subsequent sections.

Molecular mechanisms

The EWSR1-FLI1 , the hallmark oncogenic in most Ewing sarcoma cases arising from chromosomal translocation t(11;22), functions primarily as an aberrant that reprograms to promote tumorigenesis. By binding to specific enhancer elements such as GGAA repeats, EWSR1-FLI1 enhances oncogenic transcription and upregulates key target genes, including (insulin-like growth factor 1 receptor), which supports cell survival and proliferation, and (platelet-derived growth factor subunit A), which contributes to stromal interactions and tumor growth. Additionally, it induces expression of (enhancer of zeste homolog 2), a that reinforces the oncogenic state. At the cellular level, EWSR1-FLI1 drives proliferation through deregulation of the , notably by upregulating , which facilitates G1/ transition and uncontrolled . The also inhibits by suppressing lineage-specific genes, maintaining a primitive, mesenchymal-like state in tumor cells. Furthermore, it induces by promoting (VEGF) expression, enabling nutrient supply and tumor expansion in hypoxic environments. Epigenetically, EWSR1-FLI1 recruits histone modifiers, including EZH2 and components of the Polycomb repressive complex 2 (PRC2), to alter chromatin architecture. This recruitment leads to H3K27 trimethylation, resulting in chromatin remodeling and silencing of tumor-suppressive genes, while activating enhancers for pro-oncogenic loci. Such epigenetic modifications create a permissive landscape for sustained oncogene activity and block differentiation pathways. In the , EWSR1-FLI1 fosters interactions that support immune evasion and . It promotes recruitment of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which inhibit T-cell activation and create an anti-inflammatory niche. Additionally, the fusion protein activates epithelial-mesenchymal transition (EMT) pathways through downstream effectors like TGF-β signaling, enhancing motility, invasion, and distant spread to sites like lungs and bones. Resistance to therapies in Ewing sarcoma often involves persistent IGF1R signaling, where EWSR1-FLI1-mediated upregulation sustains alternative pathways like insulin receptor activation, bypassing IGF1R inhibition and promoting survival under treatment stress. This highlights the potential for targeted inhibition of EWSR1-FLI1 or its downstream effectors, such as IGF1R antagonists combined with epigenetic modulators, to disrupt these mechanisms and improve outcomes.

Clinical presentation

Signs and symptoms

Ewing sarcoma typically presents with local symptoms related to the tumor's location in or . The most common initial symptom is persistent pain at the site of the tumor, which is often described as deep, aching, and worsening at night or with activity. Swelling or a palpable mass may develop over the affected area, sometimes feeling warm or tender to the touch, and can be mistaken for or . In more advanced cases, patients may experience systemic symptoms due to inflammation or tumor burden. These include unexplained fever, fatigue, and unintentional weight loss, which can occur even without evident metastasis. Laboratory findings often reveal anemia and an elevated erythrocyte sedimentation rate (ESR), reflecting chronic inflammation. Symptoms can vary depending on the tumor's anatomical site. For tumors in long bones such as the femur or tibia, patients may develop a limp or experience a pathological fracture due to bone weakening. In cases involving the spine or pelvis, neurological deficits like weakness, numbness, or bowel/bladder dysfunction may arise from nerve compression. Extraosseous Ewing sarcoma, arising in soft tissues without bone involvement, often manifests as a painful mass with overlying redness or warmth, though pathological fractures are less common compared to osseous presentations. The nonspecific nature of these symptoms frequently leads to misdiagnosis as , trauma, or other benign conditions, contributing to an average diagnostic delay of 3 to 6 months from symptom onset. In rare instances, patients present with constitutional symptoms resembling , such as recurrent fevers, night sweats, and significant weight loss, particularly in disseminated disease.

Common sites and spread

Ewing sarcoma primarily originates in the , with approximately 50-60% of cases arising in the , most frequently involving the long bones such as the , , and . Around 20-30% of tumors develop in the , while 10% occur in the chest wall or . In 10-20% of instances, the tumor is extraosseous, manifesting in soft tissues of the , head, or . The tumor often exhibits local invasion, extending into adjacent soft tissues or neurovascular structures, and may produce skip metastases along the involved bone. variants of Ewing sarcoma are commonly located in paravertebral or retroperitoneal areas. At , 20-25% of patients present with metastatic , with the lungs being the most frequent site (70-80% of metastatic cases), followed by bones (30-45%) and (20%).

Diagnosis

Medical imaging

Medical imaging plays a crucial role in the detection, characterization, and staging of Ewing sarcoma, allowing for assessment of the primary lesion's extent, bone involvement, soft tissue components, and metastatic disease. Initial evaluation typically begins with plain , followed by advanced modalities such as (MRI), computed tomography (CT), positron emission tomography-computed tomography (PET-CT), and to provide comprehensive information for and planning. Plain radiography serves as the first-line tool for suspected lesions and often reveals characteristic features of Ewing sarcoma. Lesions typically appear as lytic areas with a permeative or moth-eaten pattern of destruction, predominantly involving the or of long bones. A prominent periosteal reaction is common, manifesting as multilayered "onion-skinning" or lamellar patterns, and a mass is frequently visible adjacent to the abnormality. These findings, while suggestive, are not specific and necessitate further to differentiate from other entities like or . MRI is considered the gold standard for evaluating the local extent of Ewing sarcoma, providing detailed visualization of tumor margins, involvement, and surrounding soft tissues. On T1-weighted sequences, the tumor appears hypointense relative to muscle, while T2-weighted images show hyperintensity, often heterogeneous due to or hemorrhage. Post-contrast enhancement is typically avid and heterogeneous, highlighting viable tumor components and aiding in the assessment of neurovascular or compartmental . MRI is essential for surgical planning by delineating the full longitudinal extent of involvement, which can span multiple bone segments. CT complements MRI by better delineating cortical bone destruction, matrix mineralization (rare in Ewing sarcoma), and calcifications within the mass. It is particularly valuable for detecting pulmonary metastases during , with chest CT recommended as standard to identify nodules or pleural effusions. Additionally, CT aids in guidance by identifying optimal access paths while avoiding critical structures. PET-CT, using 18F-fluorodeoxyglucose (FDG), is highly sensitive for Ewing sarcoma due to the tumor's avid uptake, with standardized uptake values () typically exceeding 3 in primary lesions. This modality excels at detecting distant metastases, including skeletal, , and extraskeletal sites, and is useful for assessing response by changes in metabolic activity. It often reveals a large component surrounding the bony , which is a hallmark of Ewing sarcoma. with methylene diphosphonate provides a whole-body screen for multifocal disease or skeletal metastases, showing increased uptake in all phases, though it has lower specificity compared to PET-CT. According to (NCCN) guidelines, initial staging for Ewing sarcoma should include MRI of the primary site, CT of the chest for pulmonary evaluation, and either or for systemic assessment, often combined with CT for anatomic correlation. These recommendations emphasize the multimodal approach to ensure accurate detection of the frequently large extension and potential metastatic spread at .

Pathology and biopsy

The diagnosis of Ewing sarcoma is confirmed through histopathological examination of , which provides essential details on cellular and enables ancillary testing. Core needle or open surgical is preferred, as these techniques yield sufficient material to evaluate architecture and perform molecular studies, achieving high diagnostic accuracy. is typically avoided due to its limitations in preserving architectural features and providing adequate sample volume for comprehensive analysis. Under light microscopy, Ewing sarcoma appears as diffuse sheets or lobules of uniform small round blue cells, measuring 1-2 times the size of lymphocytes, with round to oval nuclei exhibiting finely stippled chromatin, inconspicuous nucleoli, and scant clear cytoplasm. A high mitotic rate is common, and Homer-Wright rosettes—pseudorosettes with central neurofibrillary material—are observed in 10-20% of cases. Cytoplasmic deposits are a hallmark feature, staining positively with periodic acid-Schiff () and digestible by , confirming their nature. Immunohistochemistry plays a crucial role in supporting the diagnosis, with tumor cells showing strong, diffuse membranous positivity for CD99 (MIC2 antigen) in nearly all cases and in most. Nuclear expression of FLI1 is detected in 60-70% of tumors, enhancing specificity, while nuclear expression of NKX2.2 is observed in approximately 93% of cases, providing high sensitivity and supporting specificity when combined with other markers. The cells are negative for lymphoid markers such as CD45 and myogenic markers including desmin and myogenin, helping to distinguish it from mimics. Molecular testing is essential for definitive confirmation, particularly in atypical presentations, by detecting EWSR1 gene rearrangements—most frequently the EWSR1-FLI1 fusion resulting from t(11;22)—using (FISH), (RT-PCR), or next-generation sequencing (NGS). These methods identify the pathognomonic chromosomal translocations in over 95% of cases. In select instances, electron reveals neurosecretory granules (100-150 nm diameter) and microtubules, indicative of primitive neuroectodermal differentiation.

Differential diagnosis

The differential diagnosis of Ewing sarcoma primarily includes other small round blue cell tumors of and , as well as infectious and inflammatory conditions that can mimic its presentation of pain, swelling, and lytic lesions. Key considerations involve distinguishing it from primary tumors such as , which typically shows more prominent matrix production on imaging and , resulting in a mixed lytic and blastic appearance with aggressive periosteal reaction, in contrast to the purely permeative lytic lesions and onion-skin periosteal response often seen in Ewing sarcoma. must also be excluded, particularly in cases with fever or elevated inflammatory markers, where reveals features like formation, sequestra, or involucrum absent in Ewing sarcoma, alongside a sharper margin in infection compared to the ill-defined borders of the tumor. Lymphoma of bone enters the differential due to similar systemic symptoms and small cell morphology, but it more frequently demonstrates cortical disruption on MRI (87% in Ewing sarcoma vs. 60% in ) and lacks the characteristic EWSR1 gene rearrangements; instead, lymphoid markers like or CD3 are positive. Among soft tissue sarcomas, is a common mimic, especially in extraosseous sites, but it expresses muscle-specific markers such as desmin and myogenin on , whereas Ewing sarcoma shows strong membranous CD99 positivity without these markers. , typically affecting younger patients (under 5 years) with abdominal or thoracic primaries and elevated urinary catecholamines, can resemble Ewing sarcoma in adolescents but is differentiated by neural markers like NB84 and MYCN amplification rather than EWSR1-FLI1 fusion. Diagnostic challenges are compounded by overlapping age groups (Ewing sarcoma peaks at 10-20 years), sites (long bones or for Ewing vs. metaphyseal for ), and findings (lytic diaphyseal lesions in Ewing vs. blastic elements in ). aids distinction, with CD99 highly sensitive (though not specific) for Ewing sarcoma, often combined with NKX2.2 positivity, while molecular testing for EWSR1 rearrangements (present in >90% of cases) provides definitive confirmation against alternatives like CIC-DUX4 fusions in other round cell sarcomas. Rare confusions include the Askin tumor, a chest wall variant of Ewing sarcoma itself, and in adults, metastatic carcinoma, which shares but exhibits different profiles and smoking history associations. Initial misdiagnosis occurs in up to 10% of sarcoma cases with direct impact on care, often as benign or infectious processes, underscoring the need for multidisciplinary review involving , , and to integrate clinical, , and molecular data for accurate .

Treatment

Multimodal approaches

The treatment of Ewing sarcoma relies on a multimodal approach that integrates systemic with local control measures to address both microscopic and macroscopic disease. This strategy, which emerged in the through early intergroup studies, has significantly improved outcomes compared to single-modality therapies. The standard protocol involves neoadjuvant to shrink the tumor and treat potential micrometastases, followed by local control via or , and concluding with to eliminate residual disease. Risk stratification is essential for tailoring this approach, primarily distinguishing between localized and metastatic at , with informed by systems such as the Euro-EWING99 . Patients with localized generally receive the standard regimen, while those with metastatic involvement may require intensified or experimental therapies. The backbone of in these protocols is the VDC/IE regimen, consisting of alternating cycles of , , and with ifosfamide and , typically administered over 6 to 12 months. Management is coordinated by a multidisciplinary team, including medical oncologists, orthopedic surgeons, radiation oncologists, and diagnostic specialists, guided by protocols from organizations such as the (COG) and the European Society for Medical Oncology (ESMO). Recent advancements include interval compression of cycles, reducing the time between doses from three weeks to two weeks, which clinical trials have shown to enhance event-free survival without excessive toxicity.

Surgical interventions

Surgery serves as a cornerstone for local control in Ewing sarcoma, particularly for patients with localized, resectable disease following neoadjuvant to shrink the tumor and facilitate complete removal. The primary indication is to achieve microscopically negative margins (R0 resection), which is preferred when the tumor's location allows for adequate excision without excessive morbidity, aiming to eradicate residual viable disease while preserving function. This approach is integrated into , where complements systemic and, if needed, to address any microscopic remnants. In extremity lesions, which account for the majority of cases, limb-salvage resection is the standard procedure, involving wide en bloc excision of the tumor-bearing bone segment along with surrounding soft tissue, followed by reconstruction to maintain mobility and quality of life. Reconstruction techniques commonly include modular endoprosthetic replacement for rapid integration in growing patients, or biological options such as allografts or autografts for durable bony union. Amputation is now rare, performed in less than 10% of cases, typically only when neurovascular involvement or infection precludes salvage. For pelvic and spinal tumors, en bloc spondylectomy or hemipelvectomy may be employed when feasible, though these sites often limit complete resection due to proximity to vital structures. Achieving wide surgical margins of 2-5 cm beyond the tumor pseudocapsule is essential for optimal oncologic outcomes, yet this poses significant challenges in preserving critical neurovascular bundles and adjacent organs, especially in axial locations. R0 resection correlates with superior control rates, achieving approximately 90% freedom from local recurrence compared to 70% with marginal (R1) margins, underscoring the importance of precise preoperative and planning. is performed in 70-80% of localized cases where resection is viable, contributing to overall local control rates of 70-80% when combined with therapies. Common complications include surgical site infections (up to 10-15% in complex reconstructions), non-union of grafts, and functional deficits requiring extensive , with multidisciplinary follow-up essential for managing these risks. Post-operative is critical to optimize limb function and prevent long-term disability.

Chemotherapy regimens

The standard for Ewing sarcoma is VDC/IE, which alternates between , , and (VDC) and ifosfamide and (IE). In the VDC component, is administered at 1.5 mg/m² (maximum 2 mg) intravenously on day 1, at 75 mg/m² intravenously on day 1, and at 1,200 mg/m² intravenously on day 1, followed by support. The IE component involves ifosfamide at 1,800 mg/m² intravenously daily for 5 days and at 100 mg/m² intravenously daily for 5 days. Cycles are typically delivered every 2 weeks with interval compression to minimize treatment duration while maintaining efficacy. Neoadjuvant chemotherapy consists of 6 to 9 alternating cycles of VDC/, lasting approximately 12 to 18 weeks, to shrink the tumor prior to local therapy. Following surgical resection or , adjuvant chemotherapy continues with an additional 8 to 9 cycles, extending total systemic treatment to 30 to 48 weeks. This multimodal integration of chemotherapy aims to address micrometastatic disease early. Multiagent chemotherapy protocols for Ewing sarcoma emerged in the , building on earlier single-agent trials, with the INT-0091 establishing the benefit of alternating VDC and over VDC alone, improving event-free survival. The AEWS0031 trial further refined this approach through interval compression to every 2 weeks, demonstrating a 5-year event-free survival of 73% compared to 65% with standard 3-week intervals, without increased . Response to neoadjuvant is assessed histologically post-resection, where tumor exceeding 90% correlates with favorable , indicating effective cytoreduction and better long-term outcomes. For high-risk cases, such as poor initial responders or metastatic , adaptations include dose intensification of standard agents during induction and incorporation of with or with for relapsed or refractory settings to salvage response. Common side effects of VDC/IE include from , which can lead to with cumulative doses exceeding 300 mg/m², necessitating cardiac monitoring. Alkylating agents like and ifosfamide contribute to infertility risks and secondary malignancies, such as or , occurring in 2% to 5% of patients long-term. Supportive measures, including for uroprotection and growth factors for , mitigate acute toxicities.

Radiation therapy

Radiation therapy plays a crucial role in the local control of Ewing sarcoma, particularly for tumors that are inoperable, have positive surgical margins, or involve metastatic sites where is not feasible. It is often integrated into treatment plans, either as definitive for unresectable disease or as an following surgical resection with inadequate margins. In cases of metastatic Ewing sarcoma, targets both the and symptomatic metastatic lesions to alleviate pain and prevent progression. Modern techniques such as intensity-modulated (IMRT) and proton beam therapy are preferred to minimize exposure to surrounding healthy tissues, which is especially important in pediatric patients to reduce long-term morbidity. Standard dosing typically ranges from to Gy, delivered in daily fractions of 1.8 Gy, with potential boosts up to 5-10 Gy for gross residual disease. is generally administered after to target residual tumor volume, allowing for better assessment of response. The EURO-EWING 99 demonstrated that a dose of Gy is sufficient for good histological responders following adequate , supporting in select cases to balance efficacy and . is utilized in approximately 40-50% of Ewing sarcoma cases, achieving local control rates of 70-90% when used definitively or adjuvantly. Potential complications of radiation therapy in Ewing sarcoma include damage to the growth plates in children, which can lead to limb length discrepancies or musculoskeletal deformities, particularly when treating extremity tumors. Additionally, there is an elevated risk of secondary malignancies, with cumulative incidences reported at 5-10% over 15-20 years of follow-up, primarily sarcomas or leukemias arising within the radiation field. These risks underscore the importance of precise targeting and long-term in survivors.

Emerging therapies

Targeted therapies aim to exploit specific molecular vulnerabilities in Ewing sarcoma, such as the (IGF1R) pathway, which is often overexpressed due to the EWSR1-FLI1 fusion. IGF1R inhibitors like figitumumab have demonstrated tolerability and preliminary antitumor activity in s with Ewing sarcoma, including stable and partial responses in early-phase trials. A 2025 case report documented a long-term complete response to IGF1R-targeted in a with relapsed , suggesting potential for revisiting this approach in select cases. A phase III trial (COG-AEWS1221) evaluated ganitumab combined with interval-compressed in newly diagnosed metastatic Ewing sarcoma but showed no significant improvement in event-free survival. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA damage repair pathways, capitalizing on BRCA-like defects and replication stress induced by the EWSR1-FLI1 fusion in Ewing sarcoma cells. Preclinical studies have shown particular sensitivity of Ewing sarcoma to PARP inhibition, with olaparib enhancing the efficacy of trabectedin through synergistic induction of apoptosis and G2/M arrest. Clinical trials, such as SARC025, have tested PARP inhibitors like talazoparib in relapsed sarcomas, though responses in Ewing sarcoma remain modest, with challenges in translating in vitro sensitivity to durable clinical benefit. Enhancer of zeste homolog 2 (EZH2) inhibitors, including tazemetostat, address epigenetic dysregulation by the fusion protein; tazemetostat upregulates GD2 expression on tumor cells, potentially sensitizing them to immunotherapy, and is under evaluation in phase II trials for relapsed or refractory soft tissue sarcomas harboring EZH2 alterations. Immunotherapeutic strategies are gaining traction, particularly for relapsed Ewing sarcoma, where standard options yield low response rates. Checkpoint inhibitors like have shown activity in subsets of sarcomas with microsatellite instability-high (MSI-H) status, which occurs infrequently but predictably in Ewing sarcoma; the SARC028 phase II trial reported objective responses in sarcomas, including subtypes, though overall rates in Ewing-specific cohorts were around 5-18%. Chimeric antigen receptor T-cell (CAR-T) therapies targeting , a overexpressed in over 80% of Ewing sarcoma cases, have demonstrated preclinical against tumor cells, with enhanced efficacy when combined with hepatocyte growth factor (HGF) receptor blockade to overcome the immunosuppressive . Early clinical data support GD2-directed CAR-T in pediatric sarcomas, including Ewing, with ongoing trials exploring as an alternative target in fusion-driven subsets. Ongoing clinical trials emphasize combinations of these agents with standard therapies to improve outcomes in relapsed or disease. EWS-FLI1 modulators like TK216, which disrupts interactions, are in II trials combined with , showing preliminary disease control in up to 44% of patients despite modest objective response rates of 8%. Advances from 2023-2025 include investigational mRNA vaccines targeting the EWSR1-FLI1 fusion, with I trials, such as SupraVax at , initiating in late 2025 to evaluate immune responses against tumor-specific neoantigens in relapsed patients. Combined trials for Ewing sarcoma and , such as those evaluating PEN-866 with vincristine-temozolomide or with , aim to address shared pathways in pediatric sarcomas. Additionally, the INTER-EWING 1 trial, launched in 2024, is an III evaluating novel combinations for both localized and metastatic disease across pediatric and adult patients. In relapsed settings, emerging therapies have achieved response rates of 20-30% in select , such as , though broader adoption requires biomarker-driven selection. Key challenges include the inherent "undruggability" of the EWSR1-FLI1 as an intracellular , limiting direct inhibition and necessitating indirect targeting of downstream effectors. development, such as IGF1R expression or status, is essential for patient stratification to maximize efficacy and minimize toxicity in heterogeneous Ewing sarcoma populations.

Prognosis and outcomes

Survival statistics

The 5-year overall (OS) for patients with localized Ewing sarcoma is approximately 70% to 80%, while for those with metastatic at , it ranges from 30% to 40%. According to Surveillance, Epidemiology, and End Results () program data analyzed through 2021 (with updates reflecting cases up to 2020), the 5-year relative for localized is 81%, dropping to 41% for distant (metastatic) spread, and 65% overall across all stages. Survival outcomes vary significantly by age, with pediatric patients under 15 years showing higher rates—around 70% to 80% 5-year OS—compared to adults over 18, where rates are approximately 50%. Younger children, particularly those under 10, exhibit even better , with event-free survival exceeding 80% in some cohorts, attributed to differences in tumor biology and treatment response. Tumor location influences , with appendicular (extremity) sites associated with 5-year event-free (EFS) rates of about 80%, compared to 60% to 75% for pelvic or axial tumors, due to challenges in achieving local control. For patients with relapsed or refractory disease, the 5-year OS rate is generally less than 20%, though it can reach 30% to 50% in cases of isolated local recurrence treated aggressively. Over the past four decades, 5-year OS for localized Ewing sarcoma has improved from around 50% in the to 75% today, driven by refinements in systemic and local control modalities. However, global disparities persist, with survival in low-resource settings often below 50% due to limited access to . These statistics are influenced by various prognostic factors, such as disease extent and patient demographics.

Prognostic factors

Prognostic factors in Ewing sarcoma encompass a range of clinical, pathological, and molecular features that influence patient outcomes, guiding risk stratification and therapeutic decision-making. These factors help identify patients at higher risk for or poorer , with established adverse indicators including the presence of metastases at , which significantly worsens due to increased and hematogenous spread. Large tumor volume, particularly exceeding 200 mL, is another key adverse factor, correlating with more aggressive disease and reduced event-free . Poor histologic response to neoadjuvant , defined as less than 90% tumor , independently predicts higher rates of local recurrence and overall poorer . Axial tumor location, such as in the or , also adversely affects outcomes compared to extremity sites, owing to challenges in achieving local control. In contrast, several favorable prognostic indicators have been identified. Patients under of age at generally experience better outcomes, likely due to more effective response to and lower rates. Tumors located in distal are associated with improved survival, as they allow for wider surgical margins and better local control. A good histologic response to , with greater than 90% , serves as a positive predictor of long-term survival and lower relapse risk. Achievement of negative surgical margins further enhances by minimizing residual disease. Molecular features provide additional prognostic insight. While earlier studies suggested differences, recent analyses indicate no significant survival disparity between EWSR1-FLI1 and EWSR1-ERG fusion types in Ewing sarcoma. However, TP53 mutations are consistently linked to worse , increasing the risk of and reducing overall survival through impaired tumor suppression mechanisms. Risk stratification systems integrate multiple factors for clinical use. The Euro-EWING risk score incorporates tumor size, primary site, and serum (LDH) levels to classify patients, with high-risk defined by tumors larger than 8 cm or central/axial location, predicting inferior outcomes. Other clinical indicators include elevated LDH levels greater than 180 U/L, which reflect higher tumor burden and are associated with decreased survival. Presence of fever at diagnosis similarly portends poor prognosis, often indicating and aggressive disease biology.