Ewing’s sarcoma (EWS) is a rare malignant neoplasm composed of primitive neuroectodermal cells. It is most commonly found in the skeleton and is the second most common primary tumor of bone. Soft tissue Ewing’s sarcoma is much more rare, but is histologically and genetically identical to EWS of bone and is treated similarly [
As EWS carries a guarded prognosis, much effort has been made to discover prognostic factors. Reliable prognostic factors could identify particularly high-risk patients who might benefit from more aggressive treatment approaches and perhaps even investigational agents. Among possible prognostic factors, the presence of metastatic disease at the time of diagnosis, large tumor volume, and poor response to preoperative chemotherapy have been consistently shown to confer a poor prognosis [
Unlike osteosarcoma which favors the femoral and tibial metaphysis, EWS occurs in both axial and appendicular locations. In the Mayo Clinic series, approximately 44% of EWS patients had axial disease [
The purpose of this study is to report a single institution experience in the management of patients with bone and soft tissue EWS, and to investigate the importance of anatomic location as a prognostic factor. We hypothesize that axial location confers a worse prognosis than appendicular location. We further hypothesize that axial location independently predicts poor prognosis in EWS and may suggest a biologic difference between axial and appendicular EWS.
After approval from our institutional research ethics board, we searched our sarcoma database for all patients with EWS treated consecutively between 1989 and 2007. A minimum of 2-year followup was required for all patients. Seventy patients were identified. Three had incomplete records and were excluded, leaving 67 patients in the study group. Patients’ electronic records, paper charts, and radiographs (when available) were reviewed. Demographic data and details of treatment and clinical course were collected.
Axial bone EWS was defined as disease originating from the spine, sacrum, pelvis, scapula, clavicle, or rib cage. Appendicular bone EWS was defined as disease originating from any bone in the extremities. Axial soft tissue EWS was defined as originating in the head, neck, or torso. Appendicular soft tissue EWS originated from the extremities.
(The scapula and clavicle were included in the axial group because (1) they form via intramembranous ossification, (2) their geometry is clearly different than the long tubular bones of the extremities, and (3) their location overlying the chest wall is more central than the bones of the extremities.)
Staging investigations at diagnosis included computed tomography (CT) scan of the chest and total body bone scan. Some patients received total body gallium scan, magnetic resonance imaging (MRI) of the primary tumor, and bilateral bone marrow aspirations and biopsies. Sixty-six (99%) patients received chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide (total 5 cycles) alternating with etoposide and ifosfamide (total 5 cycles) for a total of 10 planned treatment cycles.
Definitive local treatment was by en bloc surgical resection whenever possible. XRT was used for lesions that were unresectable, or to treat positive resections margins following surgical management. Patients treated with definitive XRT alone received 5000 centigrays (cGy) in 25 fractions to the entire medullary cavity to cover radiographic bone marrow changes plus a 2cm margin, followed by a boost to 6000–6600 cGy in 30–33 fractions. Similarly, patients with microscopic residual disease postoperatively received 5000 cGy in 25 fractions to the tumor bed plus a 5 cm margin.
The primary outcome measure was overall survival considered from the date of diagnosis to the date of death and estimated with the Kaplan-Meier method. Patients who did not experience death over the study period were censored.
Cox proportional hazard regression models were used to estimate the effect of different variables on overall survival [
Of the 67 patients, 41 were male and 26 were female. The mean age at diagnosis was 26.9 years with a range of 12.4–77.9 years. Fifty-seven (85%) patients had bone EWS and 10 (15%) had soft tissue EWS. Thirty-four (51%) patients had axial EWS and 33 (49%) patients had appendicular EWS. The demographic, pre-treatment, and treatment characteristics of the axial and appendicular EWS groups are described in Table
Patient Information. Table
Axial EWS ( | Appendicular EWS ( | Total ( | ||
---|---|---|---|---|
Pretreatment Factors | ||||
Median Age | 25.1 | 28.7 | 26.9 | 0.23 |
No. male | 21 (62%) | 20 (61%) | 41 (61%) | 0.30 |
No. female | 13 (38%) | 13 (39%) | 26 (39%) | — |
No. bone | 31 (91%) | 26 (79%) | 57 (85%) | 0.19 |
No. soft tissue (ST) | 3 (9%) | 7 (21%) | 10 (15%) | — |
No. with metastases at diagnosis | 10 (29%) | 5 (15%) | 15 (22%) | 0.33 |
No. bone lesions over 8 cm | 21 (62%) | 17 (52%) | 38 (57%) | 0.9 |
No. bone lesions under 8 cm | 10 (29%) | 9 (27%) | 19 (28%) | — |
No. ST lesions over 5 cm | 1 (3%) | 4 (12%) | 5 (7%) | 1.0 |
No. ST lesions under 5 cm | 2 (6%) | 3 (9%) | 5 (7%) | — |
Treatment Factors | ||||
No. receiving definitive treatment | 25 (74%) | 29 (88%) | 54 (81%) | 0.22 |
No. receiving definitive surgery | 16 (47%) | 28 (85%) | 44 (66%) | 0.0018 |
No. receiving definitive XRT | 9 (26%) | 1 (3%) | 10 (15%) | 0.013 |
No. not receiving surgery or XRT | 9 (26%) | 4 (12%) | 13 (19%) | 0.22 |
No. receiving adjuvant XRT | 8 (24%) | 2 (6%) | 10 (15%) | 0.045 |
Outcome Parameters | ||||
No. positive margins | 6 (18%) | 3 (9%) | 9 (13%) | 0.0031 |
No. local recurrences | 5 (15%) | 0 (0%) | 5 (7%) | 0.053 |
No. ANED | 10 (29%) | 22 (67%) | 32 (48%) | |
No. AWED | 2 (6%) | 1 (3%) | 3 (4%) | |
No. DOD | 22 (65%) | 10 (30%) | 32 (48%) | |
% 5-year OS | 29% | 66% | 0.002 |
Overall survival for the whole group was 64% at 2 years (95% confidence interval: 53% to 77%), 47% at 5 years (95% CI: 35% to 62%), and 44% at 10 years (95% CI: 32% to 60%, Figure
Overall survival, all patients. Figure
Overall survival, axial versus appendicular. Figure
Univariate analysis revealed that axial location (
Effects of pre-treatment and treatment variables in univariable Cox proportional hazard models.
Variable/model | Univariate model | |
---|---|---|
HR [95% CI] | ||
Site (axial) | 3.07 [1.44–6.52] | 0.0022 |
Size (large) | 3.8 [1.46–9.9] | 0.0034 |
Metastasis (yes) | 4.1 [1.99–8.43] | <0.001 |
Radiation (yes) | 1.53 [0.76–3.11] | 0.23 |
Surgical margins (positive) | 3.3 [1.04–10.43] | 0.031 |
HR (hazard ratio); 95% CI (95% confidence interval).
Effect of anatomic location in univariable (model 1), multivariable analysis when adjusting for pre-treatment variables (model 2), and when adjusting for pre-treatment and treatment variables (model 3).
Variable/model | Model 1 | Model 2 | Model 3 | |||
---|---|---|---|---|---|---|
HR [95% CI] | HR [95% CI] | HR [95% CI] | ||||
Site (axial) | 3.07 [1.44–6.52] | 0.0022 | 3.11 [1.41–6.84] | 0.0048 | 4.73 [0.87–25.74] | 0.072 |
Size (large) | — | — | 3.85 [1.44–10.32] | 0.0072 | 4.35 [0.78–24.34] | 0.094 |
Metastasis (yes) | — | — | 2.9 [1.37–6.13] | 0.0055 | 2.99 [0.31–5.01] | 0.34 |
Radiation (yes) | — | — | — | — | 0.79 [0.13–5.01] | 0.81 |
Surgical margins (positive) | — | — | — | — | 2.47 [0.63–9.63] | 0.19 |
HR (hazard ratio); 95% CI (95% confidence interval).
EWS is a member of the “small round blue cell” family of tumors along with rhabdomyosarcoma and lymphoma of bone. It is thought to have a neuroectodermal origin and is characterized by a genetic translocation t(11; 22) in over 95% of cases [
We found that axial location was predictive of worse overall survival in univariate analysis, and in multivariate analyses when adjusting for pre-treatment variables. Axial skeletal location did not achieve statistical significance when adjusted for pre-treatment and treatment variables (
There were essentially equal proportions of large and small tumors in the axial and appendicular groups by AJCC criteria. It has been widely assumed that the reason for the worse prognosis of axial EWS is because these tumors are larger than those located in the appendicular skeleton. This was not the case in our study population, and our findings suggest that size alone does not explain the difference in prognosis between axial and appendicular EWS.
There was indeed a modicum of treatment heterogeneity. The axial and appendicular groups had different proportions of patients who received surgery (47% versus 85%), who had positive surgical margins (38% versus 10%), and who were treated with definitive XRT (27% versus 3%). It is entirely possible that these treatment differences contributed to the outcome of the axial and appendicular groups.
Hense et al. [
In conclusion, in our study population axial location predicted poor prognosis in EWS. This risk remains after adjusting for pre-treatment and treatment variables. Axial EWS may therefore possess a more aggressive phenotype by virtue of the microenvironmental milieu of the axial skeleton, and the interaction between EWS cells and this microenvironment. Additional clinical and basic scientific investigations will help to prove or disprove this hypothesis.