Ewing’s sarcoma family of tumors in adolescents in Beijing 2010–2019: a multicenter retrospective cohort study
Highlight box
Key findings
• Metastasis was the only significant factor associated with decreased overall survival in adolescents with Ewing’s sarcoma family of tumors (ESFTs).
What is known and what is new?
• ESFTs are aggressive cancers in children and adolescents, with metastasis linked to poor outcomes.
• This study confirms metastasis at diagnosis as a key factor in lower survival rates among Beijing adolescents, consistent with global trends. It also identifies tumor size, trunk location, lack of multimodal treatment, and delayed local therapy as predictors of worse prognosis.
What is the implication, and what should change now?
• These results highlight the importance of early detection and multimodal treatment in improving survival rates for adolescents with ESFTs and underscore the poor prognosis associated with metastatic disease.
Introduction
The Ewing’s sarcoma family of tumors (ESFTs) are rare and highly aggressive malignancies that primarily arise in bone, though they can occasionally occur in soft tissue (1). The tumors are characterized by a high propensity for local recurrence and distant metastasis (2). The precise etiology of ESFTs remains unknown. They are most frequently diagnosed in adolescents and young adults (3). In 85–90% of cases, ESFTs harbor a chromosomal translocation involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene on chromosome 22 and the ESFT-family gene (4). The majority of primary tumors originate in the bone (5). Notably, approximately one-quarter of patients present with detectable metastases at diagnosis (6). ESFTs rank the second most common primary bone tumor, following osteosarcoma (7). The current standard treatment includes intensive induction chemotherapy, followed by local therapies such as surgery, radiotherapy, or a combination of both, and concluded with adjuvant chemotherapy (8).
Many factors can affect the survival outcomes of ESFTs (9). However, regional variations in healthcare infrastructure and access to specialized oncology care may constitute unique challenges affecting patient survival outcomes. Based on our clinical experience, we anticipated that delays in local treatment may result in poor survival. Additionally, we expected that the adoption of multimodal treatment would improve patient survival. This study aimed to investigate whether these loco-regional factors, alongside known prognostic indicators such as metastasis, tumor size, and tumor size, significantly influence overall survival (OS) and event-free survival (EFS) in our cohort, thereby providing insights into the unique context of ESFT management in a major urban center in China.
The present study retrospectively collected and analyzed the clinical data from four major children’s hospitals in Beijing, China, over a 10-year period. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-392/rc).
Methods
Patients
This was a retrospective study analyzing clinical data of all adolescent ESFT patients who were treated between January 1, 2010, and December 31, 2019, at four major children’s hospitals in Beijing, China: Beijing Jishuitan Hospital, Beijing Tongren Hospital, Beijing Children’s Hospital, and Peking University First Hospital. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the ethical committee of Beijing Children’s Hospital (ethics review batch No. 2020-Z-012). All participating hospitals were informed and agreed to the study. Patient-informed consent was waived due to the retrospective nature of the data collection in this study.
The inclusion criteria were: (I) age between 10 and 18 years at the time of first admission; (II) pathologically diagnosed with ESFTs; (III) previously untreated; (IV) completed at least 2 cycles of chemotherapy. The exclusion criteria were: (I) discontinuation of treatment without disease progression; (II) unclear clinical or pathological diagnosis; (III) recurrent or progressive disease at the time of first admission.
Treatment and evaluation
Following pathological confirmation of ESFTs, tumor size, location, and metastasis were evaluated using imaging techniques. Bone marrow aspiration and biopsy were performed to evaluate for bone marrow metastasis. EWSR1 gene rearrangement was detected using fluorescent in situ hybridization (FISH). Treatment efficacy was evaluated according to the RECIST 1.1 criteria (10). The most recent follow-up time and disease status were the data endpoint. Statistical endpoints were complete remission, stable disease, progression, recurrence, and death. All children were followed up until June 30, 2022.
Statistical analysis
The number of patients treated during the study period determined the sample size. The primary outcome was OS, which was defined as the time from admission to death or loss to follow-up for any reason. EFS was defined as the time from admission to initial tumor recurrence/metastases, death, or loss to follow-up. Survival probabilities were estimated using the Kaplan-Meier method. In the survival analysis, patients who were lost to follow-up were treated as right-censored cases. Multivariate analysis was performed using the Cox regression method. Statistical analyses were performed using SPSS Version 23.0 (IBM, Armonk, NY, USA). All P values were two-sided, and a probability less than 0.05 was considered statistically significant.
Results
Patient characteristics
A total of 82 patients who met the inclusion criteria were identified. The final analysis included 79 patients, with one patient excluded for lack of treatment, and two for disease recurrences at the time of admission. Patient demographic and clinical characteristics are shown in Table 1. Males were affected more frequently than females, with a ratio of 1.82 to 1. The median age of patients was 13.5 years (range, 10.1–17.7 years). The median time from symptom onset to diagnosis was 4 months (range, 0.5–36 months). One patient had a family history of malignant tumors, and another patient had Downs syndrome. The most common initial symptom was localized pain, reported in 57 patients (72.2%), followed by local mass in 42 (53.2%), lower limb motor dysfunction in 4 (5.1%), fever in 2, and tics in 1.
Table 1
| Characteristic | n (%) |
|---|---|
| Sex | |
| Male | 51 (64.6) |
| Female | 28 (35.4) |
| Age (years) | |
| 10–15 | 56 (70.9) |
| >15 | 23 (29.1) |
| Largest tumor dimension (cm) | |
| <8 | 40 (50.6) |
| ≥8 | 32 (40.5) |
| Unknown | 7 (8.9) |
| Primary tumor site | |
| Bone | 60 (75.9) |
| Soft tissue | 19 (24.1) |
| Trunk involvement | |
| No | 34 (43.0) |
| Yes | 45 (57.0) |
| Disease extension | |
| Localized | 54 (68.4) |
| Distant metastatic | 25 (31.6) |
| Lung metastases (distant metastases) | |
| Yes | 14 (56.0) |
| No | 11 (44.0) |
| Bone metastases (distant metastases) | |
| Yes | 10 (40.0) |
| No | 15 (60.0) |
| EWSR1 gene rearrangement† | |
| Positive | 31 (39.2) |
| Negative | 2 (2.5) |
| Unknown | 46 (58.3) |
| Treatments | |
| Surgery + radiotherapy + chemotherapy | 21 (26.6) |
| Surgery + chemotherapy | 49 (62.0) |
| Radiotherapy + chemotherapy | 2 (2.5) |
| Chemotherapy alone | 7 (8.9) |
| Time from diagnosis to local treatment (surgery or radiotherapy) | |
| <18 weeks | 59 (81.9) |
| ≥18 weeks | 13 (18.1) |
†, this test became available in 2016. EWSR1, Ewing sarcoma breakpoint region 1.
Tumor characteristics
Primary lesions were found in bone in 60 patients (75.9%) and in soft tissue in 19 patients (24.1%) (Table 2). The bone tumors were predominantly located in the lower extremities, whereas the soft tissue tumors were mainly found in the trunk.
Table 2
| Sites | n (%) | Distribution |
|---|---|---|
| Bone | 60 (100.0) | |
| Trunk | 20 (33.3) | Pelvis 8, ribs 1, vertebrae 2, scapula 7 mandible 1, clavicle 1 |
| Upper extremities | 6 (10.0) | Humerus 4, metacarpale 1, radius 1 |
| Lower extremities | 34 (56.7) | Femur 19, tibia 7, fibula 4, metatarsals 3, calcaneus 1 |
| Soft tissue | 19 (100.0) | |
| Head and neck | 4 (21.1) | Paranasal sinus 1, head 2, face 1 |
| Trunk | 14 (73.7) | Spine 2, gluteal region 1, thorax 2, pleural cavity 3, perineal region 1, kidney 1, shoulder 2, pelvis 2 |
| Lower extremities | 1 (5.2) | Foot 1 |
A total of 25 (31.6%) patients had developed metastases, including 6 cases of lung metastases and 7 cases of bone metastases (Table 3). Multiple metastases were more common in bone-origin metastases compared to those originating from soft tissue (8/14, 57.2% vs. 2/11, 18.2%). Three patients (3.8%) tested positive for ESFT cells in bone marrow smears.
Table 3
| Site of metastasis | n (%) |
|---|---|
| Bone origin | 14 (100.0) |
| Lung | 3 (21.4) |
| Bone | 1 (7.1) |
| Lymph nodes | 2 (14.3) |
| Multiple metastases (≥2 sites) | 8 (57.2) |
| Lung + lymph nodes | 6 |
| Bone + lymph nodes | 1 |
| Lung + bone | 1 |
| Soft tissue origin | 11 (100.0) |
| Lung | 3 (27.3) |
| Bone | 6 (54.5) |
| Multiple metastases (≥2 sites) | 2 (18.2) |
| Lung + lymph nodes | 1 |
| Bone + lymph nodes | 1 |
The size of primary lesions was successfully measured by using imaging techniques in 72 patients, with a median diameter of 6.2 cm. The median diameter of bone tumors was 5.8 cm (range, 4–23 cm), and that of soft-tissue tumors was 8.0 cm (range, 4.2–17 cm). Patients were categorized according to the median diameter of soft-tissue lesions.
Treatment
The majority of patients, 72/79 (91.1%), received multimodal treatment, which included at least two of the following: surgery, chemotherapy, and radiotherapy. All patients received chemotherapy, with a median of 12 cycles administered. Among the 79 patients, 65 (82.3%) received neoadjuvant chemotherapy and 23 (29.1%) received radiotherapy, with a median radiation dose of 50 Gy (range, 39.6–60 Gy). The interval between diagnosis and local treatment, such as surgery or radiotherapy, exceeded 18 weeks in 13 patients (18.1%).
Survival and risk factors
The median OS was 54 months (range, 4–129 months) and that of EFS was 44 months (range, 1.5–129 months). The 5-year OS and 5-year EFS rates were 64.5% and 59.0%, respectively (Figure 1). Patients with soft-tissue lesions had higher OS (72.0% vs. 63.4%, P=0.86) and EFS rates (63.2% vs. 52.8%, P=0.89) compared to those with bone lesions; however, the differences were not statistically significant (Figure 2). Patients with metastatic disease had significantly lower OS (50.8% vs. 72.5%, P<0.001) and EFS rates (40% vs. 62.9%, P<0.001) compared to those with localized disease (Figure 3). Patients with tumor diameters less than 8 cm had significantly higher 5-year OS and EFS rates (83.9% and 61.2%, respectively) compared to those with tumors ≥8 cm (54.4% and 53.2%, respectively; P=0.03 and P=0.04).
The 5-year OS rate was 79.3% for patients who underwent surgery, compared to 44.4% for those who did not (P=0.02). For patients receiving multimodel therapy, the 5-year OS rate was 91.7%, whereas it was 0% for those who did not receive such treatment (P=0.03). Patients with trunk involvement had a 5-year OS rate of 77.8%, compared to 53.7% for those without trunk involvement (P=0.02). A longer interval (>18 weeks) from diagnosis to local treatment was associated with a significantly shorter 5-year OS rate of 62.7%, compared to 82.2% for those treated within 18 weeks (P=0.03). Finally, the 5-year OS rate for patients who received neoadjuvant chemotherapy was 73.7%, versus 60.1% for those who did not (P=0.03).
Univariate analysis showed that a maximum tumor diameter over 8 cm, metastasis, trunk as the primary tumor site, time from diagnosis to local treatment exceeding 18 weeks, and lack of multimodal treatment were significantly associated with poorer OS. However, multivariate analysis found that only metastasis was significantly associated with decreased OS (Table 4).
Table 4
| Characteristic | Univariate | Multivariate | |||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| Sex | |||||
| Male vs. female | 1.3 (0.6–2.8) | 0.51 | 0.7 (0.3–1.7) | 0.47 | |
| Age | |||||
| ≤14 vs. >14 years | 1.4 (0.6–3.0) | 0.40 | 5.5 (1.8–17.3) | 0.30 | |
| Maximum tumor diameter | |||||
| ≥8 vs. <8 cm | 2.4 (1.0–5.4) | 0.04 | 1.5 (0.6–3.98) | 0.40 | |
| Metastasis | |||||
| Yes vs. no | 6.4 (2.8–14.7) | <0.001 | 4.6 (1.8–11.7) | 0.001 | |
| Primary tumor site | |||||
| Bone vs. soft tissue | 0.9 (0.3–2.4) | 0.86 | 0.5 (0.2–1.3) | 0.15 | |
| Trunk vs. no trunk | 3.0 (1.4–6.4) | 0.004 | 1.6 (0.7–3.6) | 0.24 | |
| Time from diagnosis to local treatment | |||||
| ≥18 vs. <18 weeks | 2.9 (1.2–7.2) | 0.02 | 2.4 (0.96–6.1) | 0.06 | |
| Multimodal treatment | |||||
| No vs. yes | 4.96 (2.3–10.6) | <0.001 | 2.0 (0.8–5.0) | 0.12 | |
CI, confidence interval; HR, hazard ratio.
Recurrence and progression
Eighteen patients (22.8%) relapsed with a median time to recurrence of 13 months (range, 1.5–39 months). The recurrences were local in 6 patients and metastatic in 12 patients. Fifteen patients (83.3%) had early recurrence, defined as the time from diagnosis to recurrence being less than 2 years. In the 6 patients with local recurrence, only 3 patients received multimodal treatment. Among patients with distant relapses, 6 patients had pulmonary relapses.
The median post-recurrence survival was 13 months. Disease progression occurred in 11 patients (13.9%); of these, 5 patients had progression in bone, while 3 experienced progression in the lung and locally. No patient experienced toxicities of grade 3 or higher according to the Common Terminology Criteria of Adverse Events during treatment.
Discussion
As previously reported, males were found to be more frequently affected by ESFTs (11). In our study, we observed a male-to-female ratio of 1.82:1, indicating a higher incidence in males. However, it is important to note that soft-tissue ESFTs are more common in females. The median age of our patients was 161.5 months, which is very close to previous findings, suggesting that most cases of ESFTs manifest before the second decade of life (12).
Primary lesions of ESFTs are more commonly found in bone than in soft tissue (13). Similarly, we found a bone-to-soft-tissue ratio of primary lesions of 4.6:1. Approximately 25% of ESFT patients have metastatic disease at the time of diagnosis (14). In our study, 31.6% of the patients had metastases at the diagnosis of ESFT, and the lungs were the most common site of metastasis. Chromosomal translocation of t(11;22) (q24;q12) was detected in 31 out of 33 patients tested (93.9%), after such a test became available in 2016 in Beijing, which was higher than a previous report of 85% (15).
The current standard first-line chemotherapy regimens for ESFTs include vincristine, doxorubicin, cyclophosphamide (VDC), ifosfamide and etoposide (IE)—commonly referred to as VDC/IE—as well as the VIDE regimen (vincristine, ifosfamide, doxorubicin, and etoposide) (16,17). In our cohort, the majority of non-metastatic patients (38/52, 73.1%) did not receive radiotherapy, primarily due to concerns about the potential long-term developmental effects of radiation exposure. All patients received chemotherapy, and most (91.1%) underwent multimodal treatment. Although we anticipated that multimodal treatment would significantly improve survival—and univariate analysis supported this association—this effect did not remain statistically significant in multivariate analysis, suggesting that the observed survival benefit may be influenced by confounding factors such as disease severity or patient selection.
In addition to multimodal treatment, the most significant prognostic factor influencing survival is the presence of metastases at diagnosis (18,19). In the current study, patients who presented with metastasis at diagnosis had significantly shorter 5-year OS. Other factors that consistently and independently influence patient survival include tumor size (2,20,21). However, there is still no consensus regarding the critical cutoff diameter that might indicate a completely different prognosis of ESFTs (22). In our study, a maximum tumor diameter exceeding 8 cm was significantly associated with worse OS, which was consistent with previous findings (23).
ESFT primary lesions located in the trunk, particularly the pelvis, are linked with lower survival rates, whereas those in the extremities, particularly the distal extremities, are associated with better survival (20). This difference may be attributed to the difficulties associated with surgical procedures for tumors located in the trunk.
It has been suggested that the time to initiation of local therapy may impact prognosis of patients with ESFTs (24). In our cohort, some patients were unable to undergo local treatment due to large tumor size, disease progression, and extensive local invasion. We found that a time to local treatment exceeding 18 weeks was associated poorer prognosis; however, this association did not retain statistical significance in multivariate analysis, indicating that the observed effect may be confounded by other prognostic factors such as disease burden or treatment eligibility.
Although univariate analysis identified several potential risk factors of OS in ESFTs, only metastasis was confirmed as the only significant prognostic factor influencing survival in multivariate analysis. It was previously reported that patients with metastases limited to the lungs seem to have better survival than those with metastases to other sites (25). Our study also found that lung metastasis is associated with better survival, but the difference was not statistically significant.
There are several limitations in this study. First, its retrospective design may introduce bias and limit the ability to establish causal relationships. Second, the sample size is relatively small, which may affect the statistical power and generalizability of the findings. Additionally, the lack of detailed information on the specific multimodal treatments received by patients could influence the interpretation of the results.
Conclusions
Metastatic disease is common in children with ESFTs and is associated with poor prognosis. Multimodal treatment is essential to improve survival outcomes. Future research should focus on stratified treatment of patients with ESFTs based on prognostic factors.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-392/rc
Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-392/dss
Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-392/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-392/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the ethical committee of Beijing Children’s Hospital (ethics review batch No. 2020-Z-012). All participating hospitals were informed and agreed with the study. Patient informed consent was waived due to the retrospective nature of the data collection in this study.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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