(P 455) EXTRASKELETAL EWING SARCOMA: A MULTICENTRIC RETROSPECTIVE STUDY FROM THE ITALIAN SARCOMA GROUP

Objective: Ewing sarcomas are aggressive mesenchymal tumors arising mostly in bones but, in about 20% of patients, also in superficial or deep soft tissues (Extraskeletal Ewing Sarcoma, EES). The aim of this retrospective multicenter study was to assess clinical behavior and oncologic outcomes of patients with primary EES treated within the Italian Sarcoma Group (ISG) network in light of the new WHO classification of small round cell sarcomas.

Methods: All consecutive patients of any age with primary localized (non-recurrent, non-metastatic) EES treated with surgery between January 2002 and December 2021 at one of the following ISG sarcoma reference centers were included: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; Azienda Ospedaliera Universitaria Careggi, Florence; IRCCS Istituto Ortopedico Rizzoli, Bologna; Istituto Oncologico Veneto - IRCCS, Padua; Istituto di Candiolo IRCCS, Department of Oncology at the University of Turin, Turin; Ospedale di Prato, Prato. Patients with a primary or secondary involvement of the bone were excluded.
All diagnoses were performed by pathologists with expertise in soft tissue tumors. The study included both patients with ES with known translocation partners (EWSR1-FLI1; EWSR1-ERG; EWSR1-ETS partners; FUS-ETS partners) and patients with EWSR1 translocations and unknown partners (not possible to assess, e.g exhaustion of the sample), where morphology and immunohistochemistry were consistent with ES.
Primary study endpoints were overall survival (OS), and crude cumulative incidence of local recurrence or distant metastases (CCI of LR or DM). Univariate and multivariable analyses were performed to investigate the association between prognostic variables and the study endpoints.

Results: The study included 89 patients, 71 (79.8%) adult, 18 (20.2%) pediatric (Table 1).
Eighty-eight patients received chemotherapy (CT); of these, 17 (19.1%) received neoadjuvant CT, 60 (67.4%) neoadjuvant and adjuvant CT. Most common regimens included IVA-IE (19.5%), IVADo-IE (19.5%), and IVA (18.2%). One patient with a superficial 1cm EES was treated with surgery only.
After a median FU of 82.8 months (IQR 34.6-115.9), 5- and 8-yr OS were 0.80 (95%CI 0.71-0.90) and 0.78 (95%CI 0.69-0.88). At univariate analysis, patient’s sex, age, radiotherapy (RT) administration, time period (2002-2011 vs 2012-2021) and tumor site, depth, size, and translocation type were not associated with OS (Table 2).
Five- and 8-yr CCI of LR were 0.08 (95%CI 0.04-0.17) and 0.11 (95%CI 0.05-0.21). LR occurred as first event in 8 patients: 7 deep EES and 1 superficial EES.
Five- and 8-yr CCI of DM were 0.24 (95%CI 0.16-0.36) and 0.28 (95%CI 0.19-0.42). At univariate analysis (Table 2), patient’s age and tumor depth were associated with DM. Five-year CCI of DM was 0.61 (95%CI 0.38-0.99) in the pediatric group and 0.15 (95%CI 0.09-0.28) in the adult group (p 0.002, Fig.1A) while 5-yr CCI of DM was 0.00 in superficial and 0.31 (95%CI 0.21-0.46) in deep tumors (p 0.003, Fig.1B). Smaller tumors were associated with lower CCI of DM (p 0.074, Fig.1C). Unfavorable prognosis in pediatric group was confirmed at multivariable analysis (Fine and Gray model), after adjustment for size, depth, translocation type and RT administration (HR 2.84; 95%CI 1.19-6.78; p 0.019).
To further explore prognostic subgroups, patients were stratified by tumor size and depth. Five-year CCI of DM was 0.00 in 1-5 cm superficial EES (Group 1), 0.18 (95%CI 0.05-0.69) in 1-5 cm deep EES (Group 2), and 0.29 (95%CI 0.19-0.45) in deep EES >5cm (Group 3), p 0.054 (Fig.2A). There was a trend towards lower OS from Group 1 to Group 3 (Fig.2B, p 0.100).

Conclusion: Patients with superficial EES have a lower risk of developing DM, without a significant difference in OS. Tumor depth and size should be considered to stratify patients with EES and possibly identify favorable prognostic subgroups that might be offered less intensive medical treatments.