In this study, we found significant differences in patient demographics and other important clinical features between skeletal Ewing sarcoma and EES. We also found that patients with EES were more likely to be treated with radiotherapy and that their overall survival was worse in the first 24 months but better after 24 months compared to patients with skeletal Ewing sarcoma. The differences in tumor characteristics and clinical behavior between EES and skeletal Ewing sarcoma suggest that they may have subtle biologic differences.21
Some of these differences may arise from differences in the tumor microenvironment between Ewing sarcoma arising from the bone vs. an extraskeletal location. Our study represents a significant advance from previous studies because it is the largest and most comprehensive analysis of patient characteristics, treatment strategies, and outcomes in EES compared to skeletal Ewing sarcoma.
We clearly demonstrated that patient characteristics differ between EES and skeletal tumors. Patients with EES have a higher mean age, but also a bimodal distribution with EES more commonly found in those older than 35 and less than 5 years compared with skeletal tumors. This finding is consistent with prior reports.11
However, our study also noted other important differences between EES and skeletal tumors. Patients with EES were less likely to be male, white or have pelvic primary tumors, though more likely to have tumors arising in other axial locations. These extraskeletal tumors were more likely to have a histological classification of PNET and to be diagnosed more recently. The increased proportion of extraskeletal tumors classified as PNET may reflect changing nomenclature, as a common misconception is that soft tissue origin is synonymous with PNET histology.22
PNET histology has been described in bone tumors,23
a finding we observed in 6.4% of osseous tumors in the current study. Similarly, the increased number of cases reported in more recent years likely reflects the more recent recognition and reporting of EES as opposed to a true increase in the incidence of EES. In particular, improved cytogenetic and molecular diagnostic methods now allow for more reliable detection of genetic translocations characteristic of this disease.
The use of radiation therapy for Ewing sarcoma has evolved over the past several decades.24
Radiation has generally become less common, though still plays an important role.25
We found that radiation therapy is more common in skeletal Ewing sarcoma. This is somewhat surprising as more of these tumors were in the extremities, a site which would typically be more amenable to surgical resection. Recognizing that the use of radiation has diminished over time, we also controlled for year of diagnosis with similar results. Therefore, the reasons for this observation are unclear and require further study.
Previous smaller prior studies have suggested that outcomes for EES and skeletal Ewing sarcoma are similar.9, 12, 15, 26
Two prospective treatment studies have also shown similar outcomes for EES when treated with Ewing sarcoma protocols.1, 17
In contrast, our findings suggest that outcome differences for patients with EES compared to skeletal Ewing sarcoma are more complex. We found that patients with localized EES have an unfavorable prognosis prior to two years from initial diagnosis, but then the outcomes for EES are significantly better. These results were confirmed even after controlling for other known prognostic factors. Of note, the magnitude of this difference was much greater after 24 months, suggesting that extraskeletal site has a greater impact on long-term rather than short-term outcomes. It is possible that patients with EES are diagnosed later in their disease course compared to skeletal tumors, causing a shift in the survival curve. This hypothesis can not be tested using data available in the SEER database and will require further study. There may also be other biologic or treatment differences that account for the observed increased early mortality seen in EES. Unfortunately, additional biological and treatment data are not available from the SEER database and these possibilities can not be further elucidated by this study. Finally, we must be cautious in the conclusions we draw from this finding because our study involved patients over several decades and information about how these patients were treated is limited. Nevertheless, these outcome differences highlight the importance of further research in this area.
A main strength of this study is the large number of EES cases analyzed by using the SEER database. These results are more representative of the general population, as the database reflects many areas of the United States and many different modalities of treatment. This strategy enabled us to evaluate the largest group of EES patients published to date to our knowledge. However, there are several limitations to analyzing data from SEER, which are similar to any study using a tumor registry. We were limited to the available data in the registry, which does not provide information on cause of death, time to tumor recurrence, or chemotherapy utilization. In addition, tumor histology could not be independently confirmed. Most importantly, site of origin in either bone or soft tissue could not be confirmed. The definition of EES is not standardized. Indeed, utilizing the reported site of origin data from SEER revealed regional differences in the incidence of EES (data not shown). Nevertheless, the proportion of cases with EES (31%) out of all reported cases of Ewing sarcoma is similar to prior reports.1
In order to develop the largest cohort possible, we included patients diagnosed in the 1970s. Both the role of chemotherapy and surgical treatments evolved significantly over the past decades which could have influenced our results. It is also possible that cases of EES were misclassified in the past as it has only been recognized as a distinct entity more recently. In order to account for these changes over time, we controlled for year of diagnosis in our regression models and were able to confirm our univariate results. Another limitation is the paucity of data for tumor size in the SEER database. Tumor size is a recognized prognostic indicator in patients with Ewing sarcoma.3, 27, 28
In the SEER database, tumor size was unavailable for approximately half of the analyzed population. To address this, we performed sensitivity analyses using size data among the patients for whom these data were available and obtained similar results to regression models not including size.
Based on our findings, we conclude that there are significant differences in clinical presentation, treatment strategy, and outcomes for EES compared to skeletal Ewing sarcoma. Our findings support the idea that EES is an important subtype of Ewing sarcoma that may require different treatment strategies. Future studies should investigate the biologic basis for these differences. Additional efforts should be directed at determining optimal treatment strategies to maximize outcomes in these tumors.