1 Introduction

Ewing Sarcoma is the second most common primitive bone cancer in children and adolescents, even though a rare tumor.¹ About 95% of patients have chromosomal translocation^11,22 (q24; q12) or t^21,22 (q22; q12), which results in fusion of the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11 or the ERG gene on chromosome 21.^2,3

Extraskeletal Ewing Sarcoma (EES) was firstly described by Tefft in 1969 and accounts for about 20%–30% of Ewing Family Sarcomas, including skeletal and extraskeletal ES, peripheral Primitive Neuroectodermal Tumor (pPNET) and Askin Tumor (ES of the chest wall).⁴ EES typically occurs in the second - third decades and may develop in soft tissues at any location, most commonly at the extremities, trunk and retroperitoneum.^5,6

Historically, EES had been treated with chemotherapy protocols of rhabdomyosarcoma, although at present times it is commonly accepted that they benefit by protocols for bone Ewing sarcoma.^7,8

Studies suggest some clinical differences between extraskeletal forms and skeletal forms.^5,7,9–12 Patients with EES are older and have a more frequent location to the limbs. Nevertheless, with actual treatment protocols the prognosis remains similar, although some studies suggest better outcome for EES^9,12and some others worse.²⁸

Several studies showed correlation between prognosis and stage of the tumor (localized or metastastic), size, surgical margins, location, age and high levels of lactate dehydrogenase (LDH).^5,9,13–18

The aim of our study was to review retrospectively a series of 29 patients with EES treated between 1997 and 2018 at a single Institution to investigate prognostic factors for Overall Survival (OS) and Event Free Survival (EFS).

2 Methods and materials

Twenty-nine EES were treated at Department of Orthopaedic Oncologic in Florence between 1997 and 2018. Eight patients (27,5%) were metastatic at presentation (Table 1). Three cases classified as pPNET. There were twenty-one males and eight females (M:F ratio is 2.6:1) with a median age of 20 years (range = 1–59 yrs). The median volume of the tumor was 186.7 cm³ (range: 16–1995 cm³). Tumor volume was <100cm3 in 67% of patients and > 100 cm³ in 33%. Most EES were localized in the soft tissues of the limbs (83% vs 17%), especially in the lower limb (Table 1).

According to AJCC (American Joint Committee on Cancer Staging System) for soft tissue sarcoma, 72,5% EES were localized disease at presentation, while 27,5% presented metastatic disease (Table 1). Metastatic patients presented multiple metastases or isolated bone metastasis, while no patients had isolated lung or lymph node metastases.

Three different types of local treatment were performed: radiotherapy alone (RT) (15%), surgery alone (54%) and RT+Surgery (31%) (Table 1). When the limbs were involved, all patients underwent limb salvage surgery, except for two who wereamputated (6.8%). All treated patients received neoadjuvant and adjuvant chemotherapy according to the protocol adopted at our Institute. In one case neoadjuvant treatment was not performed and the full dose of chemotherapy protocol was administered after surgery.

At histologic examination, surgical margins resulted wide in 71% of patients, marginal in 19% and radical in 2 (10%) patients after amputation.

Good response to chemotherapy with necrosis >90% was observed in 62% of patients and poor response (necrosis <90%) in 38%. Local recurrence was 12% and distant metastases occurred in 55% of patients, 27,5% at presentation, 27,5% during follow up.

3 Results

At an average follow up of 37 months (range=1-118) 40% of patients died for progression of disease (DOD), 52% were continuosly disease-free (CDF) and 8% had no evidence of disease after treatment of local recurrence or metastasis (NED). Overall Survival at 5 years was 60% (Fig. 1) and EFS at 5-yrs was 56%(Fig. 2).

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Fig. 1 5-yrs Overall Survival in extra-skeletal Ewing Sarcoma.

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Fig. 2 5-yrs Event Free Survival in extra-skeletal Ewing Sarcoma.

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Five years Overall Survival was 44.4% in metastatic patients and 68.8% in non--metastatic EES (p = 0.08) (Fig. 4).

A better 5-yrs EFS was found in patients with localized disease at onset (68.8%) compared to metastatic EES (33.3%) (p = 0.042) (Fig. 3).

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Fig. 3 5-yrs Event Free Survival in metastastic EES and not.

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Fig. 4 5-yrs Overall Survival in metastastic EES and not.

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Local treatment that offered the best results was the combination of surgery and radiotherapy. Patients treated only with surgical resection had a 5-yrs OS of 64.3%, while OS was 85.7% in radiotherapy + surgery group; no patients treated with RT alone survived, but 75% of these patients presented with multiple metastases (p = 0.017) (Fig. 5).

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Fig. 5 5-yrs Overall Survival based on the treatment.

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Accordingly EFS at 5 years, resulted a better after surgery associated to radiotherapy (70%) compared to only surgery (59%), even if this was not statistically significant (p = 0,0964).

Tumor volume was a significant prognostic factor. OS at 5 years was 76,9% with volume <100 cm³, while it was 28,6% with volume >100 cm³ (p = 0.032). Differently the volume was not significant for EFS (p = 0,1870) even if we reported better trend with size < 100cm3 (73% at 5) than >100cm3 (33% at 5 yrs).

No difference was observed considering gender: 5-yrs OS in females was 71.4%, while in males 55.6% (p = -0.54).

Dividing patients into two age groups (below and above 20 years old) we didn't find statistically significant differences. OS was 70% with age <20 years while it was 53.3% in age >20 (p = 0.388). Patients with age <20 years presented 61% of EFS at 5 years, whereas in patients with age > 20 years, EFS was 53%. This result was not significant (p = 0.6355).

The necrosis induced by neoadjuvant treatment was not a significative prognostic factor in our series. The OS was 75% in presence of necrosis >90%, 69,2% in ≤90% necrosis. (p = 0.7). The necrosis was not significant for EFS (p = 0.8941).

In addition, surgical margins were a significant prognostic factor for OS at 5-yrs (p = 0.01), but not for EFS with 75% at 5 in adequate margin and inadequate margin.

Local recurrence did not correlate with Overall Survival (p = 0.1009), whereas distant metastasis resulted significant (p = 0.0013).

4 Discussion

Extraskeletal Ewing Sarcoma is a rare tumor and only few series are reported in literature. Among Ewing family tumors, the incidence of EES is variable, ranging from 9 to 47%.¹⁹ In our series, the incidence of extraskeletal origin was 13.4% on a total of 216 patients with Ewing family tumors. In pediatric population EES usually occurs in older children and adolescents if compared to bone ES. Authors reported an incidence of 50–91% of cases in age >15 years old.^13–19

The median age in our patients was 20 years with a very variable range (range = 1–59). We divided EES into two groups based on age <20 and >20, finding no differences in outcome between the two groups (p = 0.388).

In our series 83% of EES were localized at the extremities and 27,5% of cases were metastastic at presentation. Tumoral size and volume were repoerted as prognostic factors favoring the appearance of metastasis.¹⁹ In our series volume >100 cm³ influenced OS (p = 0.032), but not the EFS (p = 0.1870). However, large size was associated with a higher probability to develop metastases.

Differently from others Authors we did not observe isolated lung metastases at presentation but metastatic EES had isolated bone metastases or multiple metastases. Although there is a common genetic condition with bone Ewing sarcoma, the use of the same therapeutic approach for EES is still debated.²⁰

Treatment strategy is based on combining systemic chemotherapy with surgery, considering radiotherapy in selected cases. Similarly to bone Ewing sarcoma, systemic chemotherapy is a key element in the treatment of EES²¹ The application of neo-adjuvant chemotherapy in the treatment of EES has greatly improved survival at 5 years from 10 to 65%.^22,23 In the Mayo Clinic series, survival rose from 28% before 1970 to 46% before 1990 in EES with age > 50.¹⁴ Association of four drugs, vincristine-adriamycin- cyclophosphamide-actinomycin-D seems to be the most effective for EES.²⁴

The integration of iphosfamide and etoposide significantly improved prognosis in patients with high-risk localized disease.^23,25 The goal of neoadjuvant therapy is to eliminate visible micro-metastases and to decrease the size of primary tumors making easier surgical excision with adequate margin. The local treatment of the disease is still controversial, since there are no trials comparing radiotherapy with surgery. After surgical resection, in EES local recurrence rate of <10% was reported. Surgery is the main tool for local control and it might be able to prevent the late recurrence of chemo-resistant cells. Another advantage of surgical resection of the primary tumor is the opportunity to evaluate the amount of necrosis induced by neoadjuvant chemotherapy.⁶

Ewing Sarcoma is a radiosensitive tumor and isolated radiotherapy can be used as local treatment. However, Kushner et al. demonstrated a disease progression of 78% at the primary site in 14 patients treated with chemotherapy and radiotherapy alone as local tratment.²⁶ Differently, Kinsella et al. suggested that wide surgical resection is not mandatory to achieve good local control reporting a 64% disease free survival in 11 patients treated with radiotherapy – chemotherapy(13).

Multimodal therapy given by the association of chemotherapy, surgery and radiotherapy is commonly accepted the best treatment for EES.¹³ In our experience, the best local treatment is represented by the combination of surgery and radiotherapy. Overall survival at 5yrs was 64,5% in patients treated with the association surgery + radiotherapy as local tratment. No patient treated with RT alone survived although 75% of these patients were multi-metastastic at onset. (p = 0.017).

In a serie of 12 patients trated with chemotherapy and radiotheapy alone, El Weshi et al. reported an EFS of 12% and a disease progression in 50% of patients, concluding that surgery is the best option for local control. They also observed better results in 24 patients treated with chemotherapy-surgery-radiotherapy combination with an OS of 68% at 5 years vs 39% of EES treated with chemotherapy and surgery alone (19). In our series EFS (local and distant control) at 5 years was better with surgery associated to radiotherapy (70%) if compared to only surgery (59%), even if this was not statistically significant (p = 0,0964).

When combine with surgery, radiotherapy can be performed in a neoadjuvant and adjuvant setting. Preoperative radiotherapy should be considered in case of poor response to chemotherapy at imaging or in case of high risk of positive surgical margins with surgical excision. Adjuvant postoperative radiotherapy is recommended in case of positive margins, in presence of residual disease or in case of poor histological response to preoperative chemotherapy¹³

Surgical margins, in our experience, were a significant prognostic factor for OS (p = 0.01), but not for EFS. Wide resection with negative margins should be the goal of EES. Several studies have pointed out the prognostic value of adequate surgical resection and its impact on OS. Rud et al. showed 69% of OS in 13 patients treated with wide or radical resection. El Welshi documented 70% of OS in 24 patients undergoing surgical resection with negative microscopic margins.^14,19

Tumoral necrosis after neoadjuvant chemotherapy was not a significant prognostic factor in our series, differently from other authors who emphasized the importance of this element. Rosito et al. showed a significant difference in 3-year EFS with 49% in poor responders vs 97% in patients with good necrosis.²⁷ Similarly, El Weshi et al. reported 70% of EFS at 5 years in good responders and 31% in poor responders.¹⁹

In conclusion, EES is a rare soft tissue sarcoma making part of the Ewing family sarcoma, showing a high propensity to develop local recurrence and distant metastasis. A multidisciplinary approach including systemic and local tratment is recommended in EES. Systemic chemotherapy is the mainstay of treatment, following by local tratment with surgery and/or radiotherapy. The association of surgery and radiation therapy showed the best results in our series in local and systemic control. Inadequate surgical margins and tumoral volume resulted negative prognostic factors. The poor histological response to neoadjuvant chemotherapy could be an indication to a more aggressive treatment, although it was not a significant prognostic factor in our series. The presence of metastases at onset influenced negatively overall survival. Adequate surgical margins significantly correleted with overall survival in our series.