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Clinicodemographic characteristics of extraosseous Ewing sarcoma: A comparative meta-analysis of pediatric and adult patients
∗Corresponding author: Maher Ghandour. mghandourmd@gmail.com
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Evidence suggests different presentation patterns and prognosis of extraosseous Ewing Sarcoma (EES) based on age. Thus, we carried out this study to test the difference between children and adult EES cases regarding clinicodemographic characteristics and prognosis.
A total of 4 databases were explored yielding 18 relevant studies for data synthesis. Outcomes included the comparison of demographic and clinical characteristics as well as prognosis between children and adults with EES. Log odds ratio (logOR) and its 95% confidence interval (CI) were pooled across studies. Statistical models/methods were selected based on heterogeneity.
Our analysis included a total of 1261 children and 1256 adults. When we compared these two age categories, we did not observe a significant difference in the risk of developing EES [logOR = −0.13; 95% CI: −0.65: 0.39; I2 = 88.42%]. No significant differences regarding gender, tumor location, and size (≤5 vs. >5 cm), EWSR1 positivity, or management modality. We did not observe significant difference regarding clinical outcomes, such as 5-year overall survival and event-free survival, recurrence, mortality, no evidence of disease, and secondary metastasis.
Our findings highlight the absence of an association between the age category of patients and the incidence of EES, as well as its clinical outcomes.
Keywords
Extraosseous ewing sarcoma
Pediatric
Children
Extra-skeletal
Adults
Clinical outcomes
1 Introduction
Extraosseous Ewing Sarcoma (EES), also known as extraskeletal Ewing Sarcoma (ES), is a rare disease entity, belonging to the ES family of tumors which includes three other types: ES of the bone, peripheral primitive neuroectodermal tumors, and Askin tumor.1–4 Although rare, EES is gaining attention over the past decade as it accounts for up to 20% of patients with ES.5
EES has very low, as it accounts for 0.4 cases per million individuals.4 Some studies reported that adolescents and young adults are more likely to develop EES compared to older individuals.6–8 On the other hand, a prospective study indicated that the occurrence of EES is higher among older patients (>40 years of age).9 Furthermore, a recent epidemiological report showed that EES exhibited a bimodal age distribution pattern, displaying two peaks of incidence in the course of a lifetime: children (<5 years) and adults (≥35 years).10 As compared to ES of the bone, the likelihood of developing EES increases with age. This denotes an association between EES and age, unlike ES originating from the bone.10–12 However, these observations are based on empirical evidence and reflect the inconsistency in the incidence of EES across ages.
A recent systematic review highlighted the presentation patterns in pediatric EES cases alone.13 The study reported that children account for 30% of EES cases, with the thorax and extremities being the most common sites. In terms of prognosis, the study reported 69% of children with EES had a 5-year overall survival and no evidence of disease.13
The management of EES mostly depends on tumor resectability, rather than age. However, these recommendations are often based on individual experience due to the rarity of the disease with little-to-no regard given to patients’ age. The National Comprehensive Cancer Network (NCCN) confirmed that a standardized management protocol is still lacking.14,15 Therefore, studies highlighting the clinical presentation, management, and prognosis of EES are still required.
Given the lack of evidence highlighting the role of age on the occurrence of EES along with its clinicodemographic characteristics in each age group, we conducted this meta-analysis. We hypothesize that EES has different incidence, clinicodemographic characteristics, and clinical outcomes in children (<21 years of age) compared to adults (>21 years of age).
2 Materials and methods
2.1 Research design and PICOS framework
We performed a systematic screening of observational and experimental studies (study design) that assessed the clinicodemographic/clinical characteristics (outcome of interest) of adult and pediatric patients with EES (population of interest). No interventions nor comparison groups were included; however, between-study comparison based on age (adult vs. children) was conducted. This review was performed following the PRISMA guidelines for systematic reviews and meta-analyses.16
2.2 Inclusion/exclusion criteria
Studies were included if they were entirely compliant with our selection criteria: (1) observational (cohort, case-control, or case series) or experimental (interventional) in design, (2) included patients with EES, and (3) reported the clinicodemographic characteristics and management outcomes. On the other hand, studies containing one or more of the following points were excluded: (1) animal studies, (2) studies that only included non-EES patients, (3) studies including EES patients but without specifying patients’ age, (4) duplicated studies, and (5) studies with incomplete data or studied based on secondary research (i.e., review articles, comments, guidelines, viewpoints, etc.).
2.3 Information sources
We identified studies through systematic searches of the following databases: PubMed, Scopus, Web of Science, and Google Scholar (only the first 200 citations were considered based on relevance).17 The search included a combination of keywords and terms related to the condition being studied. The search strategy was formulated with the help of a medical librarian. The search was conducted on July 28th, 20,223, and we did not impose any restrictions on language of publication or publication status. Importantly, the database search was updated on July 2023 to identify any newly published relevant studies. The database search was supplemented by a manual searh. We checked the reference lists of all of the studies assessed for eligibility and any relevant systematic reviews identified. We also examined any relevant retraction statements and errata for included studies.
2.4 Search strategy
The detailed search strategy per each database is provided in (Supplementary Table 1).
2.5 Selection process
Two study authors carried out this step, and whenever differences arose, the corresponding author was consulted. Eligible papers or those whose eligibility was unclear were marked for retrieval, while papers that did not meet our eligibility criteria were not retrieved. Duplicated results were removed prior to title and abstract screening with the use of EndNote software. The full texts of studies passing the title/abstract phase were retrieved for further validation. Meanwhile, studies without an available full text were excluded. Articles that did not match our predefined criteria were excluded and recorded in our PRISMA diagram.
2.6 Data collection and data items
Before the formatting of an extraction tool, the full texts of eligible articles were carefully read and all outcomes were appropriately listed. This step helped in making a comprehensive, thorough sheet that covers all of the items discussed in this review. Extracted data included study setting, population of interest, their sociodemographic characteristics (particularly age), study methodology, and the origin of Ewing sarcoma (extraskeletal or skeletal). Importantly, for analysis purposes, we categorized studies into two groups based on age: adults (18 years of age or more) and children (below 18 years of age). Study outcomes were also extracted including survival data, disease recurrence, no evidence of disease (NED), or secondary metastasis to organs. Similar to the screening process, two authors performed the data extraction and the accuracy of these data were ensured by the corresponding author. Conflicts in data extraction resolved by discussion with all authors and determined by consensus.
2.7 Data analysis
Data extracted from individual studies were synthesized. STATA software was used to run all meta-analyses. The statistical method was selected according to the observed statistical heterogeneity. The random-effects model was selected as significant statistical heterogeneity was encountered in the analysis. The heterogeneity was confirmed by I2 statistic >50% with a P-value <0.05. Upon comparing both adult and pediatric EES cases, we calculated the log odds ratio (logOR) for dichotomous outcomes and the mean difference for continuous outcomes.
3 Results
3.1 Results of the database search
A complete description of the systematic search and article selection results is provided in Supplementary Fig. 1. The systematic search helped identify 2611 citations, of which 179 were excluded due to article duplication. From the remaining studies, 2432 citations were exported into a screening sheet. Following the reading of the titles and abstracts of these papers, 2156 were deemed ineligible for inclusion. The full texts of the remaining articles were then retrieved for further eligibility checking; however, we could not find the full texts of six of them. During this process, 231 studies were found ineligible for further assessment due to the following reasons: Ewing sarcoma of skeletal origin (23 studies), single reports (73 studies), duplication (3 studies), EES cases with undetermined age (3 studies), non-original research (4 studies), mixed-age patients (91 studies), irrelevant patient population “undetermined origin of Ewing Sarcoma” (5 studies), non-Ewing sarcoma (23 studies), and secondary research articles (6 studies). Although an updated search along with a manual search of references was attempted, no additional relevant studies were found. This resulted a total of 18 articles eligible for further evaluation.18–35
3.2 Characteristics of analyzed articles
The analysis of the 18 included reports included the assessment of 2517 EES patients. According to the age category, 1261 were children and 1256 were adults. The characteristics of these studies and assessed patients are provided in Table 1. Most studies were performed in the US (8 studies), while other studies were conducted in the United Kingdom (2 studies), Italy (3 studies), Korea (1 study), India (2 studies), Germany (1 study), and China (1 study). In terms of design, four studies were case series, 12 were retrospective cohorts “mainly chart reviews”, one was a secondary analysis of three prospective studies, and one was a secondary analysis of the SEER database. The definition of each age group (children and adults), with the range of values, is summarized in Table 1 (see Fig. 1).
| Author (YOP) | Country | Design | Sample | FU (months) | Age Range | |
| Children | Adults | |||||
| Banerjee (1997)18 | UK | Case series | 8 | 5–12 | 9–17 | 21–36 |
| Biswas (2014)19 | India | Chart review | 374 | 25a | ≤18 | >18 |
| Boyce‐Fappiano (2021)20 | USA | Chart review | 60 | 74a | ≤18 | >18 |
| Casanova (2007)21 | Italy | Case series | 52 | 120a | 1–18 | >18 |
| Chen (2019)22 | USA | Chart review | 31 | 24.8 | <20 | ≥20 |
| Chiang (2017)23 | USA | Chart review | 19 | NR | 12–16 | 24–68 |
| Deshpande (2021)24 | India | Case series | 8 | 15–43 | 1–13 | 33 |
| Gupta (2010)25 | USA | Chart review | 53 | 46.8a | 0.3–16.2 | 16.7–66.5 |
| Koka (2021)26 | USA | Case series | 8 | 52.63 | 2–8 | 22–42 |
| Koscielniak (2021)27 | Germany | Secondary analysis of 3 studies | 243 | 84a | 1–18 | >18 |
| Lee (2010)28 | Korea | Chart review | 94 | 24.9 | ≤18 | >18 |
| Livellara (2022)29 | Italy | Chart review | 57 | 5–349 | ≤18 | >18 |
| Muratori (2020)30 | Italy | Chart review | 29 | 37a | <20 | >20 |
| Murugan (2018)31 | USA | Chart review | 23 | 5–156 | 8–19 | 21–70 |
| Pradhan (2011)32 | UK | Chart review | 253 | 87 | <16 | ≥16 |
| Tarek (2020)33 | USA | Chart review | 30 | 0.9 | 1–19 | 21–50 |
| Verma (2017)34 | USA | SEER-based study | 415 | NR | 0–18 | 19–89 |
| Xie (2010)35 | China | Chart review | 18 | NR | <18 | ≥18 |
3.3 Patients’ demographic data
3.3.1 Age
Seventeen studies compared the occurrence rate of EES among children (1261 cases) and adults (1256 cases) [Fig. 2]. The meta-analysis revealed no statistically significant difference in the risk of having EES between children and adults [logOR = −0.13; 95% CI: −0.65: 0.39; I2 = 88.42%]. The reported estimate did not change at any point upon performing sensitivity analysis [Supplementary Fig. 2].
3.3.2 Gender
Seven studies reported the occurrence rate of EES between pediatric and adult patients based on gender (336 males and 301 females) [Supplementary Figs. 3 and 4]. Among female cases, our meta-analysis showed no statistically significant differences between children and adults regarding the occurrence of EES [logOR = −0.28; 95% CI: −0.81: 0.25, I2 = 0%]. Similarly, among males, we noted no significant changes in the risk of EES between children and adults [logOR = 0.37; 95% CI: −0.25: 0.99; I2 = 0%]. Based on the absence of heterogeneity, we did not perform sensitivity analysis.
3.4 Clinical characteristics
3.4.1 Location of EES
Among included studies, only seven reported the location of EES based on the age group of affected patients. Due to the unavailability of sufficient data, the conduct of a meta-analysis in this regard was not applicable. A summary of the locations and percentages of presentation among children and adults with EES is presented in Supplementary Table 2.
3.4.2 Tumor size
Two studies reported the difference in the occurrence rate of EES between children and adults based on the size of the tumor. These studies compared EES rates in two categories: ≤5 cm and >5 cm. In the first group (≤5 cm), no statistically significant changes in the risk of EES were observed between children and adults [logOR = −0.9; 95% CI: −0.89: 0.70, I2 = 57.32%] [Supplementary Fig. 5]. In the latter group (>5 cm), we did not observe any statistically significant difference in the risk of EES between children and adults [logOR = 0.09; 95% CI: −0.58: 0.76; I2 = 0%] [Supplementary Fig. 6].
3.4.3 EWSR1
Four studies compared the positivity of EWSR1 between children (21 cases) and adults (50 cases) with EES [Fig. 5]. Our meta-analysis revealed no statistically significant difference in EWSR positivity between children and adults with EES [logOR = 0.20; 95% CI: −0.68: 1.08; I2 = 0%].
3.4.4 Management modalities
Several studies reported how EES was managed among children and adult patients, respectively. Noteworthy, no studies reported the administration of preoperative radiotherapy before surgery or radiotherapy alone. Meanwhile, only one study reported the performance of surgery alone [75% vs. 66.6% for children and adults, respectively]23 and concurrent chemotherapy and radiotherapy [57.1% vs. 0% for children and adults, respectively].33
Five studies highlighted the performance of combined surgery and chemotherapy among EES cases. Our meta-analysis revealed no statistically significant change in the odds of combined surgery and chemotherapy between children and adults [logOR = 0.0, 95% CI: −0.82: 0.83; I2 = 0%] [Supplementary Fig. 7]. In three studies, postoperative radiotherapy was reported [Supplementary Fig. 8]. Our meta-analysis revealed no significant difference in the odds of postoperative radiotherapy between children and adults with EES [logOR = 0.21; 95% CI: −1.11: 1.53; I2 = 0%].
3.5 Clinical outcomes (prognosis)
3.5.1 5-Year overall survival
Seven studies reported the 5-year OS between children (388 cases) and adults (232 cases) with EES [Fig. 3]. In our meta-analysis, we observed no statistically significant difference in the 5-year OS between children and adults with EES [logOR = −0.04; 95% CI: −0.35: 0.27, I2 = 0%].
3.5.2 5-Year event-free survival
Two studies reported the 5-year EFS between children (49 cases) and adults (40 cases) with EES [Fig. 4]. In our meta-analysis, we observed no statistically significant difference in the 5-year EFS between children and adults with EES [logOR = −0.22; 95% CI: −0.97: 0.52, I2 = 0%].
3.5.3 Mortality
Seven studies reported the recurrence rate between children (252 cases) and adults (84 cases) with EES [Fig. 5]. In our meta-analysis, we observed no statistically significant difference in the rate of NED between children and adults with EES [logOR = −0.04; 95% CI: −0.70: 0.62, I2 = 0%].
3.5.4 No evidence of disease
Seven studies reported the recurrence rate between children (262 cases) and adults (111 cases) with EES [Supplementary Fig. 9]. In our meta-analysis, we observed no statistically significant difference in the rate of NED between children and adults with EES [logOR = 0.10; 95% CI: −0.38: 0.58, I2 = 0%].
3.5.5 Recurrence
Three studies reported the recurrence rate between children (17 cases) and adults (44 cases) with EES [Fig. 6]. In our meta-analysis, we observed no statistically significant difference in the recurrence rate between children and adults with EES [logOR = −0.24; 95% CI: −1.42: 0.94, I2 = 0%].
3.5.6 Secondary metastasis
Three studies reported the rate of metastasis between children (231 cases) and adults (43 cases) with EES [Supplementary Fig. 10]. In our meta-analysis, we observed no statistically significant difference in the rate of metastasis between children and adults with EES [logOR = −0.21; 95% CI: −1.04: 0.62, I2 = 0%].
4 Discussion
In a previous review, we reported the clinicodemographic characteristics of EES in the pediatric population13; however, differences in presentation patterns and clinical outcomes between pediatric and adult patients are still unclear. This meta-analysis provides the largest body of evidence regarding the incidence, presentation patterns, and clinical outcomes of EES among patients of different age groups: children (<21 years of age) and adults (>21 years of age). Our study, based on the analysis of 18 studies and 2517 EES cases, revealed no significant association between age group and incidence of EES. This might be different from ES of the bone, since original reports highlight a significant correlation between age and ES incidence, with patients of 0–20 years of age having higher rates compared to 21–40 and 40–60 years (67% vs. 42% vs. 37%), respectively. Important to mention, the substantial heterogeneity that we encountered in our analysis makes our evidence non-conclusive. Additionally, due to the lack of relevant data, we could not assess different age groups, which could have resulted in different findings, as highlighted in a previous report.36
Among patients with EES, gender has shown a correlation with the occurrence of this tumor; some reports have shown female predominance,37 while others reported male predominance.38 However, such findings should be carefully interpreted due to the lack of sample size with sufficient power to detect significant differences. In our meta-analysis, we detected no significant contrast in the incidence of EES between adults and children stratified by gender. This observation was of moderate certainty given the large number of included patients and the lack of heterogeneity. However, more research in this regard, controlling for the confounding effect of potential covariates such as tumor characteristics (i.e., site and size) is still warranted.39
On the other hand, findings of EES location among children and adult cases were not conclusive given the scarcity of relevant data as the biggest proportion of available evidence reports the tumor location in the overall population (mixed age) with no stratification according to age. In this regard, the data presented here were extracted from case series, reporting such data on a case-by-case basis. That being said, the most commonly reported sites were the skin/subcutaneous tissue,18 kidneys,31 cranial or intracranial tissue,32 female genital tract,24 the orbits,23 head and neck,26 the pelvis,27 the spine,27 the thorax,27 the abdomen,27 and both extremities.27 No meaningful findings could be reached from such data [Supplementary Table 2].
The tumor size has been previously believed to play a role in the presentation pattern of ES and its clinical outcomes, such as metastasis, with a higher likelihood of worse clinical outcomes in larger tumors.39–41 Since the main outcome of our analysis was to determine the difference in tumor size between different age groups, our search and analysis were not focused on identifying a correlation between tumor size and EES occurrence overall. Instead, our analysis of tumors of ≤5 or >5 cm in size revealed no significant change in the presentation with EES among children and adult cases, although previous research indicates a correlation between age and tumor size, showing increased size with increased age.42 Of note, this analysis was based only on 2 studies with small sample sizes; thus, more research is needed to confirm our observation.
ES breakpoint region 1 (EWSR1) is considered one of the most frequently involved genes in sarcoma translocation. It encompasses a diagnostic value in identifying ES of soft tissues, with fluorescence in situ hybridization (FISH) being a confirmatory tool. In our study, we tested the difference in the positivity rate of EWSR1 between children and adults with EES; however, we did not detect any statistically significant differences. This highlights that EWSR1 positivity occurs regardless of age. However, due to the limited sample size, more research is still needed.
The optimum management of EES remains a great challenge, particularly in different age groups, given the rarity of this tumor, the variability in clinical presentation, and the difference in patients’ characteristics.43 Additionally, the lack of clinical trials, secondary to the unavailability of enough sample size, exacerbates this problem and hinders the process of developing a solid evidence-based protocol for managing different cases. Overall, in our review, the management varied greatly among studies, with surgeons opting for surgery alone,23 concurrent chemotherapy and radiotherapy,33 or combined surgery and chemotherapy.18,24,31 No differences were observed in our meta-analysis regarding the latter as a management modality for EES between children and adults. Due to the lack of enough data, we could not analyze nor detect any varying patterns in the management of EES according to age.
Our previous research supported the high rate of NED and 5-year overall survival of 69%, with moderate and low rates of mortality (29%), recurrence (35%), and secondary metastasis (16%) among pediatric cases of EES, respectively. However, in this study, we did not detect significant differences between children and adults in all of the aforementioned outcomes. Despite evidence suggesting an association between age and EES metastasis and prognosis,36,41 our findings are confined to children vs. adults alone. However, such findings could differ within each age category upon using other age groups. This points warrants further investigation while accounting for other risk factors of prognosis, such as gender or the location and size of the tumor.40
4.1 Limitations and future directions
Our meta-analysis provides novel findings, reflecting the absence of an association between patients’ age group and EES incidence, clinicodemographic characteristics, and clinical outcomes. However, several aspects should be given into consideration when interpreting these results. First, the encountered heterogeneity in the original analysis of the association between age and EES incidence reflects the lack of precision, which limits the applicability of our findings to the whole EES patient population. Importantly, the range of age in each age group was variable, which could be the major contributor to the observed clinical and statistical heterogeneity. In addition, a recent large-scale study of 2780 patients indicated that patients 40 years of age or higher are significantly more likely to have extraosseous ES as compared to those with <40 years old.36 Increased age was correlated to a higher likelihood of metastasis in other reports.41 The use of the cutoff point of 21 years in our analysis could be nonoptimal. Therefore, further studies are needed to validate these findings. Second, most evidence analyzed in this review ranged from case series to retrospective chart reviews with a lack of prospective studies that could have provided better evidence and resulted in evidence with higher certainty. Finally, the small sample size and the scarcity of data regarding certain aspects (i.e., tumor location and size) highlight the need for future research to study the effect of these points on the occurrence and clinical outcomes of EES.
5 Conclusions
Our findings highlight the absence of association between the occurrence of extraosseous Ewing sarcoma and patients’ age group (children vs. adults). There are also no significant differences in presentation patterns between adults and children with EES regarding gender, clinical characteristics, and prognosis. Further studies are still needed to validate these results.
Funding
No funding was provided for this research.
Author contribution
Maher Ghandour: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, and Writing – original draft. Doumit Semaan and Axel Horsch: Supervision, Project administration, Software, Resources, Validation, Visualization, and Writing – review & editing. Karl Semaan, Eddy Saad, and Ralph Abdallah: Investigation, Methodology, Visualization, and Writing – original draft.
Competing interests
The authors declare no competing interests associated with the conduct of this work.
Data availability statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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