Imaging plays a central role in the diagnosis, staging, treatment monitoring and surveillance of EES (20). However, the imaging characteristics of EES are non-specific (20–22). EES can be diagnosed via ultrasonography (US), computed tomography (CT) or MR imaging, with each modality having its own specific indications (20).

With US, EES usually appears as a heterogenous mass of low echogenicity with intratumor flow signals on a Doppler study. With CT, EES presents as a large sharply demarcated mass with similar intensity to the surrounding muscles. Post-contrast medium enhancement reveals areas of necrosis, while the surrounding viable contour appears enhanced and heterogeneous (20). Calcification is present in only 10% of cases, appearing faint and amorphous (20). With MR imaging, EES has low-to-intermediate signal intensity on T1-weighted sequences and displays high signal intensity on T2-weighted images, with variable post-contrast enhancement (Fig. 1) (20–23). MR imaging is performed prior to biopsy to help determine the optimal biopsy site and to avoid the distortion caused by post-biopsy changes (24). This is also recommended for restaging purposes prior to local control, as the tumor may have receded or progressed during neo-adjuvant chemotherapy (7).

MR imaging and CT scans are accurate for local staging of malignant bone and soft-tissue tumors (7). However, MR imaging is used more frequently due to its high detection sensitivity for soft tissue contrast, as well as its ability to avoid radiation exposure from CT scans (7).

In addition to local staging of the primary tumor, imaging is also used to detect the presence of metastatic disease. CT scans of the chest are superior to conventional radiographs in detecting lung metastasis. Intravenous contrast is not required unless there is hilar, mediastinal or chest wall involvement that may require further delineation of these regions. With chest CT, metastatic legions are typically round, ovoid, sharply demarcated and located in the lung periphery (7). Notably, it is recommended to perform a chest CT prior to biopsy to avoid the stimulation of metastasis due to atelectasis secondary to general anesthesia (7).

Bone scans are also recommended for detection of bone metastasis at presentation. If regions of increased uptake are noted on the scan, radiographs are performed to further confirm the presence of metastasis (7). This may be followed by cross-sectional imaging modalities of these areas if the diagnosis of metastasis is uncertain (7). FDG-PET appears to be superior to bone scans for the detection of bone metastasis in ES (8,9). FDG-PET is also used to assess chemotherapeutic response and detect recurrent disease (7). Gerth et al (25) reported that PET/CT is sensitive (87%) and specific (97%) for detecting distant metastasis, with an accuracy of 94%.

Overall, definitive diagnosis is made with a CT-guided or ultrasound-guided core-needle biopsy, as well as pathological examination of the resected surgical specimen (26).

EES is a soft, multilobulated, gray-yellow tumor, whose diameter rarely exceeds 10 cm (18). EES can contain cystic, hemorrhagic or necrotic areas; however, calcifications are rare (18). Microscopically, EES appears as monomorphic, small, round blue cells that contain large spherical nuclei, inconspicuous nucleoli and indistinct cytoplasmic borders (27). These cells lack extracellular matrix and have low mitotic activity, albeit necrotic areas are commonly observed (Figs. 2 and 3) (27).

Immunohistochemistry is used in addition to light microscopy to diagnosis EES (18). A spectrum of immunohistochemical markers are used to study EES since no marker is pathognomonic (18). These markers include CD99 antigen, which is a single-chain type-1 glycoprotein that is highly sensitive but not specific, S-100 protein and synaptophysin, both of which are neural markers, and FLI1, which was recently discovered as a DNA-binding transcription factor that is involved in t(11;22) translocation and has higher specificity than CD99 (18,28).

The use of pathology and immunohistochemistry for the diagnosis of EES is sufficient in most cases. However, molecular genetic analysis via reverse transcriptase (RT) PCR or fluorescence in-situ hybridization (FISH) add an additional diagnostic domain that is essential in unusual variants. The two most common chromosomal translocations specific to EES and ESFT are t(11;22)(q24;q12) and t(21;22)(q22;q12) (29). Translocation t(11;22)(q24;q12) is present in 90% of all cases, which causes a fusion between the FLI gene on 11q24 and the EWSR1 gene on 22q12, creating an EWS/FLI-1 transcript that has the DNA binding domain of FLI-1 instead of the RNA-binding domain of EWS (29). Conversely, translocation t(21;22)(q22;q12) fuses EWSR1 and ERG, which is another DNA-binding protein (30), creating an oncogenic transcription factor that inhibits apoptosis (30). Less common translocations have also been reported, all of which involve the EWSR1 gene on chromosome 22 (30).

The use of systemic chemotherapy in the treatment of localized ESFT has increased the 5-year survival rate from 5 to 10%, to >65%, which is primarily due to the elimination of micrometastases (3). To the best of our knowledge, Rud et al (34) was the first to report on the importance of multiagent chemotherapy in the treatment of patients with EES, demonstrating that the survival rate increased from 28%, before 1970, to 48%, after 1970. In addition, Raney et al (10) reported a 10-year survival rate of 61–77% following multiagent chemotherapy. According to Bacci et al (11), neoadjuvant and adjuvant chemotherapies exhibited comparable results in patients with localized disease. Overall, chemotherapy improves the overall survival rates and decreases the likelihood of recurrence following surgery (12).

The current regimens include alternating vincristine-doxorubicin, cyclophosphamide and ifosfamide-etoposide cycles every 3 weeks (Tables I and II) (35). Womer et al (35) demonstrated that patients who received the same chemotherapy regimen every 2 weeks instead of 3 weeks, known as interval compression, exhibited a better event-free survival rate (73 vs. 65%) (36). Although chemotherapy programs are essential and have proven effective, chemotherapy alone without surgery and/or radiotherapy is insufficient as a treatment option (36).

EES is radiosensitive; however, the use of radiotherapy alone for local control has proved less effective over the years. This is due to advancements in surgical techniques for limb salvage, as well as the adverse effects of radiotherapy and the high incidence of local recurrence (>30–35%). Nonetheless, studies comparing surgery with radiotherapy may have overlooked the importance of selection factors dictating local therapy decisions (4,32). Surgery is performed in cases where marginal or wide resection is possible (32,37). Resectable lesions are usually small, peripheral in location and have a good response to induction chemotherapy (36). Conversely, irradiated lesions are often large, central in location and have a poor response to induction chemotherapy (36). The ability to obtain adequate negative margins has the strongest influence on local control of malignancy. Wider margins are required when the response to chemotherapy is not adequate (4,32). When it is not possible to obtain wide margins due to the presence of fixed structures, such as vessels and/or nerves, postoperative radiotherapy can be implemented for better local control (4,32).

The overall 5-year survival rate is better in patients who undergo complete resection, with wide surgical margins compared with suboptimal margins (13). However, if the tumor is not resectable with clear margins (spine or skull) or if surgery would involve vital fixed structures, definitive radiotherapy can be implemented (14,37).

According to the European Cooperative Ewing Sarcoma Studies (CESS) and European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) trials (38), intralesional resection with radiotherapy did not result in a superior local control rate compared with radiotherapy alone. In such cases, surgery can be avoided in favor of radiotherapy (38). Currently, definitive radiotherapy is only indicated for inoperable lesions, with a recommended dose of 54–55 Gy depending on the involved site (10,39). However, larger tumors may require higher doses (10,39).

Metastatic disease or unresectable recurrent disease is treated with the same approach as localized disease but carries a worse prognosis (32). In such cases, chemotherapy is an option, with the limited benefit of extending progression-free survival (23). In patients with lung metastasis, whole lung irradiation has been demonstrated to offer survival benefit (40). Chemotherapy regimens similar to localized disease can be used in such cases but are less effective (32).