# Sclerosing Epithelioid Fibrosarcoma (SEF) versus Low Grade Fibromyxoid Sarcoma (LGFMS): Presentation and outcome in the nationwide NETSARC+ series of 330 patients over 13 years

JY Blay, C. Tlemsani, M. Toulmonde, A. Italiano, M. Rios, E. Bompas, T.

Valentin, F. Duffaud, Lr Le Nail, S. Watson, et al.

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JY Blay, C. Tlemsani, M. Toulmonde, A. Italiano, M. Rios, et al. Sclerosing Epithelioid Fibrosarcoma (SEF) versus Low Grade Fibromyxoid Sarcoma (LGFMS): Presentation and outcome in the nationwide NETSARC+ series of 330 patients over 13 years. European Journal of Cancer, 2024, 196, pp.113454. 10.1016/j.ejca.2023.113454. hal-04894144

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Original Research

Sclerosing Epithelioid Fibrosarcoma (SEF) versus Low Grade Fibromyxoid Sarcoma (LGFMS): Presentation and outcome in the nationwide NETSARC+ series of 330 patients over 13 years

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JY Blay<sup>a, *, 1</sup>, C. Tlemsani<sup>b</sup>, M. Toulmonde<sup>c</sup>, A. Italiano<sup>c</sup>, M. Rios<sup>d</sup>, E. Bompas<sup>c</sup>, T. Valentin<sup>f</sup>, F. Duffaud<sup>g</sup>, LR Le Nail<sup>h</sup>, S. Watson<sup>i</sup>, N. Firmin<sup>j</sup>, P. Dubray-Longeras<sup>k</sup>, M. Ropars<sup>l</sup>, C. Perrin<sup>m</sup>, A. Hervieu<sup>n</sup>, C. Lebbe<sup>o</sup>, E. Saada-Bouzid<sup>p</sup>, P. Soibinet<sup>q</sup>, F. Fiorenza<sup>r</sup>, F. Bertucci<sup>s</sup>, P. Boudou<sup>b</sup>, G. Vaz<sup>a</sup>, S. Bonvalot<sup>b</sup>, C. Honoré<sup>t</sup>, P. Marec-Berard<sup>a</sup>, V. Minard<sup>t</sup>, M. Cleirec<sup>u</sup>, D. Biau<sup>b</sup>, P. Meeus<sup>a</sup>, A. Babinet<sup>b</sup>, V. Dumaine<sup>b</sup>, S. Carriere<sup>j</sup>, M. Fau<sup>c</sup>, G. Decanter<sup>v, w</sup>, F. Gouin<sup>a</sup>, C. Ngo<sup>c</sup>, F. Le Loarer<sup>b</sup>, M. Karanian<sup>a</sup>, A. Meurgey<sup>a</sup>, A. Dufresne<sup>a</sup>, M. Brahmi<sup>a</sup>, C. Chemin-Airiau<sup>a</sup>, F. Ducimetiere<sup>a, 2</sup>, N. Penel<sup>v, w</sup>, A. Le Cesne<sup>r</sup>, on behalf of the NETSARC/REPPS/RESOS and French Sarcoma Group- Groupe d'Etude des Tumeurs Osseuses (GSF-GETO) networks

ARTICLE INFO

Keywords:

Low grade fibromyxoid sarcoma
Sclerosing epithelioid fibrosarcoma
Sarcoma
Rare cancers

A B S T R A C T

Sclerosing Epithelioid Fibrosarcoma (SEF) and Low Grade Fibromyxoid Sarcoma (LGFMS) are ultrarare sarcomas sharing common translocations whose natural history are not well known. We report on the nationwide exhaustive series of 330 patients with SEF or LGFMS in NETSARC+ since 2010.

<footnote><sup>a</sup> Centre Léon Bérard & Université Claude Bernard, Lyon, France</footnote>

<footnote><sup>b</sup> Hopital Cochin, Paris, France</footnote>

<footnote><sup>c</sup> Departement of Medical Oncology, Institut Bergonié, Bordeaux, France</footnote>

<footnote><sup>d</sup> Institut Cancerologie Lorraine, Centre Alexis Vautrin, Nancy, France</footnote>

<footnote><sup>e</sup> Department of Medical Oncology, Institut de Cancerologie Ouest Nantes, France</footnote>

<footnote><sup>f</sup> Institut Claudius Regaud & Institut Universitaire de Cancerologie, Oncopole, Toulouse, France</footnote>

<footnote><sup>g</sup> La Timone University Hospital, Marseille, France</footnote>

<footnote><sup>h</sup> CHU Tours, 37000 Tours, France</footnote>

<footnote><sup>i</sup> Dept of Medical Oncology, Institut Curie & INSERM U830, Institut Curie Research Center, Paris, France</footnote>

<footnote><sup>j</sup> Institut de Cancérologie de Montpellier, Montpellier, France</footnote>

<footnote><sup>k</sup> Centre Jean Perrin/ERTICa EA 4677, Clermont-Ferrand, France</footnote>

<footnote><sup>l</sup> Eugene Marquis Comprehensive Cancer Center, France</footnote>

<footnote><sup>m</sup> CHU, Rennes, France</footnote>

<footnote><sup>n</sup> Centre George François Leclerc, Dijon, France</footnote>

<footnote><sup>o</sup> Centre Georges François Leclerc, Dijon, France</footnote>

<footnote><sup>p</sup> Dermato-Oncology Unit, Saint Louis Hospital, Paris, France</footnote>

<footnote><sup>q</sup> Centre Antoine-Lacassagne, Nice, France</footnote>

<footnote><sup>r</sup> Institut J Godinot Reims, France</footnote>

<footnote><sup>s</sup> Institut Paoli-Calmettes, Marseille, France</footnote>

<footnote><sup>t</sup> Gustave Roussy Cancer Campus, Villejuif, France</footnote>

<footnote><sup>u</sup> Dept pédiatrie, CHU Nantes, France</footnote>

<footnote><sup>v</sup> Univ. Lille, CHU Lille, ULR 2694 - Metrics: Evaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France</footnote>

<footnote><sup>w</sup> Department of Medical Oncology, Centre Oscar Lambret, Lille, France</footnote>

<footnote>* Correspondence to: Department of Medical Oncology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cedex 08, France.</footnote>

<footnote>E-mail addresses: jean-yves.blay@lyon.unicancer.fr (J. Blay), morgane.cleirec@chu-nantes.fr (M. Cleirec), francoise.ducimetiere@lyon.unicancer.fr (F. Ducimetiere).</footnote>

<footnote n="1">¹ The Network Director of NETSARC+</footnote>

<footnote n="2">² The Deputy Director of NETSARC+</footnote>
**Patients and methods:** NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB). Since 2010, (i) pathological review has been mandatory for sarcoma, and (ii) tumour/patients' characteristics have been collected in the NETSARC+ nationwide database. The characteristics of patients with SEF and LGFMS and their outcome are compared.

**Results:** 35/73 (48%) and 125/257 (49%) of patients with SEF and LGFMS were female. More visceral, bone and trunk primary sites were observed in SEF (p < 0.001). 30% of SEF vs 4% of LGFMS patients had metastasis at diagnosis (p < 0.0001). Median size of the primary tumor was 51 mm (range 10–90) for LGFMS vs 80 (20–320) for SEF (p < 0.001). Median age for LGFMS patients was 12 years younger than that of SEF patients (43 [range 4–98] vs 55 [range 10–91], p < 0.001). Neoadjuvant treatment was more often given to SEF (16% vs 9%, p = 0.05). More patients with LGFMS were operated first in reference centers (51% vs 26%, p < 0.001). The R0 rate on the operative specimen was 41% in LGFMS vs 16% in SEF (p < 0.001). Median event-free survival (EFS) of patients with SEF and LGFMS were 32 vs 136 months (p < 0.0001). The median overall survival (OS) was not reached. Fifty-months OS was 93% vs 81% for LGFMS vs SEF (p = 0.05). Median OS was 77 months after first relapse, similar for SEF and LGFMS.

In multivariate analysis, age, tumor size, metastasis at diagnosis were independent prognostic factors for OS in LGFMS.

**Conclusions:** Although sharing close molecular alterations, SEF and LGFMS have a different natural history, clinical presentation and outcome, with a higher risk of metastatic relapse in SEF. Survival after relapse is longer than with other sarcomas, and similar for SEF and LGFMS.

# 1. Introduction

Sclerosing Epithelioid Fibrosarcoma (SEF) and Low Grade Fibromyxoid Sarcoma (LGFMS) are ultrarare sarcomas (incidence 0.15 and 0.51/10⁶/year respectively) [1] sharing common molecular alterations. Their natural history and optimal treatment are not established in the absence of large multicentric series.

Though microscopically different tumors, LGFMS and SEF share similar immunohistochemical profiles, e.g. expression of vimentin and cytoplasmic MUC4 expression [10,13–19]. Both are associated with structurally related translocations and chimeric fusions, involving *CREB3L1/CREB3L2*, with a member of the FET protein family (*FUS* or *EWSR1*) [19–26]. LGFMS most often present with *FUS::CREB3L2*, more rarely with *FUS::CREB3L1* and rarer cases harbor the *EWSR1::CREB3L1* fusion, while SEF present *EWSR1::CREB3L1* or *EWSR1::CREB3L2* fusion genes. Hybrid SEF/LGFMS tumors are more likely to harbor the *FUS::CREB3L2* fusion confirming the nosological proximity of these tumors [19–26].

LGFMS is reported to be associated with a low risk of relapse and death [2–13], while SEF has been reported to present a more aggressive behavior [14–18] but overall little is known on the compared natural history and optimal treatment of these two very rare entities [27,28]. Following our report on the incidence of these two sarcomas [1], we report here on the nationwide exhaustive series of 330 patients with SEF or LGFMS included in NETSARC+ since 2010.

# 2. Patients and methods

## 2.1. The network

The NETSARC+ network includes 26 expert sarcoma centers, organizing multidisciplinary tumor board (MDTB) with sarcoma specialized pathologist(s), radiologist(s), surgeon(s), radiation oncologist(s), medical oncologist(s), molecular biologist(s), orthopedist(s), and pediatrician(s) [1,29,30]. All sarcoma or suspected sarcoma patient cases presented to the MDTB of these centers are recorded in the NETSARC+ database, by a dedicated team of clinical research assistant (CRAs), supervised by three Coordinating centers (Centre Leon Bérard, Institut Gustave Roussy, Institut Bergonié). Patient files may be presented to the MDTB before any diagnostic procedure, before initial biopsy, before primary surgery, after primary surgery, at relapse, and/or in case of inclusion in a clinical trial. A monitoring of centers' activity is performed by the three coordinating centers on a regular basis.

## 2.2. The NETSARC database and the CONTICABASE

The NETSARC database exhaustively describes the incident and prevalent population of all sarcoma patients in France, using a cross comparison of the pathological review database (pathology review of sarcoma is mandatory in France) and the clinical database. NETSARC database includes information on the diagnostic and initial treatment procedures, and patients' outcome including survival and relapse but this database includes a limited set of data, on purpose, describing patients and tumors characteristics, surgery, relapse and survival [29–31]. For the present study, the database was extracted on January 2023 for the period from January 2010 to December 2022.

The CONTICABASE is a sub-set of NETSARC+, which includes all patients managed since the initial diagnosis in one of the NETSARC+ centers. It contains more detailed information on the nature of treatment, responses, and follow-up, as well as molecular characteristics. It is extensively used for publications of the group [30,31]. The 116 patients included during the same period within the Conticabase were extracted and all 12 patients with documented systemic treatment were analyzed.

These databases were approved by the French Ethic Committee and Agency in charge of non-interventional trials: the “Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé” (CCTIRS: number of approval 09.594)” and the “Commission.”

Nationale Informatique et Liberte (CNIL: number of approval 909510)”. As part of being managed in the network and to have their data added to the NETSARC registry, the patients have the opportunity to opt-out for the analysis of their data in national and academic research programs.

## 2.3. Statistical analyses

The categorical data were summarized by the frequencies and percentages, and the continuous covariates were summarized with median, range and numbers of observations. The statistical test used for comparison was a chi-square (or a Fisher) test for categorical covariates, without adjustment for multiple comparisons. The diagnostic date was the date of first histological diagnosis (biopsy or first surgery). Overall survival (OS) was calculated from the date of diagnosis to the date of last follow-up or death. Event-free survival (EFS) was computed from the date of diagnosis to the date of the last follow-up or the date of the first local or metastatic relapse, progression or death, whichever came first. Progression-free survival (PFS) was computed from the date of diagnosis of metastasis to the date of the last follow-up or the date of local or distant progression or death, whichever came first. Relapse-free survival
(RFS) was computed for M0 patients at diagnosis from the date of diagnosis to the date of the last follow-up or the date of the first local or metastatic relapse or death whichever came first.

A composite parameter, time to progression, death or to next treatment, was used to describe the outcome of patients receiving systemic treatment.

Survival curves were plotted using a Kaplan-Meier method. Survival curves were compared using the log-rank test. Multivariate analysis for OS included prognostic factors identified as significant in univariate analysis, e.g. sex, presence of metastasis, and presence of bone lesions. Cox proportional hazard model was used for the multivariate analysis, introducing parameters correlated to survival with a p value p < 0.10 in univariate analysis. Factors included in the multivariate model were identified by a backward selection procedure which entails including all the covariates in the model and removing those whose p-value is higher than 0.10 one at a time. At each step of the model, all included variables were tested and removed if they were no longer associated with the outcome considering a 5% type one error (p-value ≥0.05). Therapeutic parameters (immediate surgery yes/no; immediate medical treatment yes/no) were subsequently introduced in the model along with independent clinical prognostic factors. All statistical tests were two-sided. All statistical analyses were performed using SPSS (version 22.0).

# 3. Results

## 3.1. Patients' characteristics

A total of 330 patients were identified, including 73 SEF and 257 LGFMS patients. Table 1 presents the characteristics of the patients. 35/ 73 (47.9%) and 125/257(48,8%) of patients with SEF and LGFMS were female. Metastases at diagnosis were present in 27.4% of SEF versus 4.3% of LGFMS (p < 0.001). Median size of the primary tumor was larger in SEF, 80 mm (range 20–320) vs 50 (range 11–260) in LGFMS (p < 0.001). Median age at diagnosis for LGFMS patients was 43 years (range 4–98), 12 years younger than median age of SEF patients, which was 55 years (range 10–91, p < 0.001). 27/253 (10.7%) with LGFMS and 1/73 (1.4%) of patients with SEF were aged under 17 (p = 0.01). There were more visceral, bone and trunk primary sites in SEF (p < 0.001). Very few occurred in irradiated field or during pregnancy (Table 1).

## 3.2. Local treatments

Table 1 shows the clinical management of patients. No significant difference was observed between the two subtypes in terms of rate of biopsies, and presentation to a reference center prior to MDTB. A marginally higher proportion of patients with SEF received neoadjuvant treatment (16.4% vs 8.6%, p = 0.05). As expected, patients to whom neoadjuvant treatment was provided had significantly larger tumors (median 100 mm vs 52 mm, p < 0.001). Surgery of the primary tumor was conducted more frequently in LGFMS vs SEF because of a higher proportion of metastatic tumors in SEF (Table 1). Among operated patients, a larger proportion of patients with LGFMS were operated first in reference centers (p = 0.002).

The quality of surgery also differed between the two subtypes. Overall for both, the quality of surgery was significantly better in reference centers vs non-specialized centers. Of note, the rate of R0 resection for the first surgery rate was 41% vs 16% in LGFMS vs SEF (p < 0.001) respectively (Table 1). The difference was significant in reference centers only. R0 rate was inferior to 20% for both SEF and LGFMS in non-reference centers. Re-excisions were performed in 18% of the patients, similarly in SEF and LGFMS. The final quality of resection, taking in account the re-excision, remained significantly better in LGFMS (Table 1).

<table><caption>**Table 1**

Patients clinical presentation and management.</caption><thead><tr><th></th><th>All*</th><th>SEF</th><th>LGFMS</th><th>p value</th></tr></thead><tbody><tr><td><strong>Presentation</strong></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Gender</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>F</td><td>160<br>(48.5%)</td><td>35<br>(47.9%)</td><td>125<br>(48.6%)</td><td rowspan="2">0.92</td></tr><tr><td>M</td><td>170<br>(51.5%)</td><td>38<br>(52.1%)</td><td>132<br>(51.4%)</td></tr><tr><td>Age (median range)</td><td>45 (4–98)</td><td>55<br>(10–91)</td><td>43 (4–98)</td><td rowspan="2">0.000</td></tr><tr><td>Size (median, range)</td><td>60<br>(11–400)</td><td>52<br>(11–400)</td><td>80<br>(20–320)</td></tr><tr><td>Metastatic</td><td>31 (9.4%)</td><td>20<br>(27.4%)</td><td>11 (4.3%)</td><td rowspan="2">0.000</td></tr><tr><td>Deep seated</td><td>291<br>(89.9%)</td><td>3 (95.9%)</td><td>221<br>(86.0%)</td></tr><tr><td><strong>Sites</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Lower limb</td><td>109<br>(33.0%)</td><td>12<br>(16.4%)</td><td>97<br>(37.7%)</td><td></td></tr><tr><td>Upper limb</td><td>38<br>(11.5%)</td><td>8 (11.0%)</td><td>30<br>(11.7%)</td><td></td></tr><tr><td>Trunk wall</td><td>101<br>(30.6%)</td><td>27<br>(37.0%)</td><td>74<br>(28.8%)</td><td></td></tr><tr><td>Internal trunk</td><td>48<br>(14.5%)</td><td>13<br>(17.8%)</td><td>35<br>(13.6%)</td><td></td></tr><tr><td>Head &amp; Neck</td><td>28 (8.5%)</td><td>9 (12.3%)</td><td>19 (7.4%)</td><td></td></tr><tr><td>Other &amp; bone</td><td>6 (1.8%)</td><td>4 (5.5%)</td><td>2 (0.8%)</td><td rowspan="2">0.000</td></tr><tr><td>Previous cancer</td><td>28 (8.5%)</td><td>21 (8.2%)</td><td>7 (7.6%)</td></tr><tr><td>Irradiated field</td><td>2 (0.6%)</td><td>1 (0.4%)</td><td>1 (1.4%)</td><td>0.7</td></tr><tr><td><strong>Diagnosis during</strong></td><td></td><td></td><td></td><td>0.11</td></tr><tr><td>Pregnancy</td><td>2 (0.6%)</td><td>1 (0.4%)</td><td>1 (1.4%)</td><td>0.11</td></tr><tr><td><strong>Management</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Biopsy before treatment</td><td>230<br>(69.7%)</td><td>50<br>(68.5%)</td><td>180 (70.0)</td><td>0.80</td></tr><tr><td>MDTB before Treatment</td><td>60<br>(18.2%)</td><td>9 (12.3%)</td><td>51<br>(19.8%)</td><td>0.14</td></tr><tr><td>Neoadjuvant treatment</td><td>34<br>(10.3%)</td><td>12<br>(16.4%)</td><td>22 (8.6%)</td><td>0.05</td></tr><tr><td>Surgery of the primary</td><td>293<br>(88.8%)</td><td>57<br>(78.1%)</td><td>236<br>(91.8%)</td><td rowspan="2">0.001</td></tr><tr><td>In M0 tumors</td><td>279<br>(93.3%)</td><td>49<br>(92.5%)</td><td>230<br>(93.5%)</td></tr><tr><td>First surgery in reference Centers</td><td>151<br>(53.5%)</td><td>19<br>(34.5%)</td><td>132<br>(58.1%)</td><td rowspan="2">0.002</td></tr><tr><td><strong>Quality of first resection</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>- R0</td><td>118<br>(35.8%)</td><td>12<br>(16.4%)</td><td>106<br>(41.2%)</td><td></td></tr><tr><td>- R1</td><td>95 (28.8)</td><td>16<br>(21.9%)</td><td>79<br>(30.7%)</td><td></td></tr><tr><td>- R2</td><td>20 (6.1%)</td><td>9 (12.3%)</td><td>11 (4.3%)</td><td></td></tr><tr><td>- R unknown</td><td>60<br>(18.2%)</td><td>20<br>(27.4%)</td><td>40<br>(15.6%)</td><td></td></tr><tr><td>- Not operated</td><td>37<br>(11.5%)</td><td>16<br>(21.9%)</td><td>21 (8.6%)</td><td rowspan="2">0.000</td></tr><tr><td><strong>Quality of first resection in reference centers**</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>- R0</td><td>93<br>(61.6%)</td><td>6 (31.6%)</td><td>87<br>(65.9%)</td><td></td></tr><tr><td>- R1</td><td>36<br>(23.8%)</td><td>5 (26.3%)</td><td>31<br>(23.5%)</td><td></td></tr><tr><td>- R2</td><td>5 (3.3%)</td><td>2 (10.5%)</td><td>3 (2.3%)</td><td></td></tr><tr><td>- R unknown</td><td>17<br>(11.3%)</td><td>6 (31.6%)</td><td>11 (8.3%)</td><td rowspan="2">0.002</td></tr><tr><td>- Not operated</td><td>0</td><td>0</td><td>0</td></tr><tr><td><strong>Quality of first resection outside reference centers**</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>- R0</td><td>25<br>(17.6%)</td><td>6 (15.8%)</td><td>19<br>(18.3%)</td><td></td></tr><tr><td>- R1</td><td>59<br>(45.0%)</td><td>11<br>(30.6%)</td><td>48<br>(50.5%)</td><td></td></tr><tr><td>- R2</td><td>15<br>(11.5%)</td><td>7 (19.4%)</td><td>8 (8.4%)</td><td></td></tr><tr><td>- R unknown</td><td>43<br>(30.3%)</td><td>14<br>(36.8%)</td><td>29<br>(27.9%)</td><td rowspan="2">0.112</td></tr><tr><td>- Not operated</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th></th><th>All*</th><th>SEF</th><th>LGFMS</th><th>p value</th></tr></thead><tbody><tr><td>Reexcision**</td><td>52<br>(17.7%)</td><td>13<br>(22.8%)</td><td>39<br>(16.5%)</td><td>0.64</td></tr><tr><td>Quality of final resection</td><td></td><td></td><td></td><td></td></tr><tr><td>- R0</td><td>158<br>(47.9%)</td><td>19<br>(26.0%)</td><td>139<br>(54.1%)</td><td></td></tr><tr><td>- R1</td><td>62<br>(18.9%)</td><td>10<br>(13.7%)</td><td>52<br>(20.2%)</td><td></td></tr><tr><td>- R2</td><td>14 (4.2%)</td><td>8 (11.0%)</td><td>6 (2.3%)</td><td></td></tr><tr><td>- R unknown</td><td>59<br>(17.6%)</td><td>20<br>(27.4%)</td><td>39<br>(14.8%)</td><td></td></tr><tr><td>- Not operated</td><td>37<br>(11.2%)</td><td>16<br>(21.9%)</td><td>21 (8.2%)</td><td>0.000</td></tr></tbody></table>

### 3.3. Survival

A large proportion of patients progressed or relapsed for both disesases. The median EFS of patients with SEF and LGFMS were 32 vs 136 months (p < 0.0001). The median OS was not reached. Survival at 50-

months was 93% in LGFMS vs 81% in SEF (p = 0.05). Local relapse-free survival was not significantly different in the two groups (Fig. 1C), but metastasis-free survival in M0 patients was significantly worse in patients with SEF (Fig. 1D).

Nevertheless, the survival and progression-free survival (PFS) from the date of metastasis were similar in the two sarcoma subtypes (Fig. 2A), with a median PFS close to 18 months and a median survival of 43 and 65 months for SEF and LGFMS, superior to those reported in more common soft tissue sarcoma subtypes [29,30]. For M0 patients at diagnosis, EFS was significantly worse in patients with SEF, while OS did not differ between SEF and LGFMS. After similar quality of final resection (e.g. R0, or R1), the risk of progression was consistently higher in SEF for R0, R1, R2, and R unknown subgroups (Fig. 2E & F), with only minor superiority of EFS for the R0 and R1 subgroups vs R2 and unknown subgroups for SEF.

Table 2 shows the independent prognostic factors for survival and DFS i) in the whole series, ii) in SEF, and iii) in LGFMS. In multivariate analysis for EFS, SEF histological sub-type, tumor size, and R0 resection were independently correlated to survival (Table 3). For the LGFMS subtype, small size, R0 resection and surgery in reference center were

A : Overall survival

<figure><img src="image_4.png" /></figure>

B : Event-free survival

<figure><img src="image_5.png" /></figure>

C : Local-relapse free survival

<figure><img src="image_6.png" /></figure>

D : Metastasis-free survival

<figure><img src="image_7.png" /><figcaption>**Fig. 1.** Survival and progression free survival of SEF and LGFMS. A: Overall survival of SEF (green) and LGFMS (blue) (logrank p value, p = 0.05); B: Progression free survival of SEF (green) and LGFMS (blue) (logrank p value, p < 0.001). C: Local relapse free survival of SEF (green) and LGFMS (blue) (logrank p value, p = 0.32) of operated patients.</figcaption></figure>
A : PFS from diagnosis in M1 patients

<figure><img src="image_8.png" /></figure>

B : RFS from diagnosis in M0 patients

<figure><img src="image_9.png" /></figure>

C : OS from the diagnosis of metastases

<figure><img src="image_10.png" /></figure>

D : OS from diagnosis in M0 patients*

<figure><img src="image_11.png" /></figure>

E : SEF : RFS and resection status

<figure><img src="image_12.png" /></figure>

F : LGFMS : RFS and resection status

<figure><img src="image_13.png" /></figure>

Fig. 2. Survival of M1 and M0 SEF and LGFMS. A: PFS from diagnosis in M1 patients with SEF (green) and LGFMS (blue) (logrank p value, p = 0.70); B: EFS from diagnosis in M0 patients with SEF (green) and LGFMS (blue) (logrank p value, p < 0.001). C: Overall survival of SEF (green) and LGFMS (blue) from the diagnosis of metastases (logrank p value, p = 0.82); D: Overall survival of M0 patients with SEF (green) and LGFMS (blue) from the diagnosis (logrank p value, p = 0.13). E and F: Relapse free survival of operated patients according to the documented quality of surgery in M0 patients (E: SEF, F: LGFMS): R0: blue, R1: green, R2: brown, R unknown: purple (logrank p = 0.002).
<table><caption>**Table 2**
Multivariate analysis of prognostic factors for PFS or OS.</caption><thead><tr><th>LGFMS & SEF</th><th>HR (95% CI)</th><th>p</th></tr></thead><tbody><tr><td><strong>Overall survival</strong></td><td></td><td></td></tr><tr><td>Metastases at diagnosis</td><td>6.07 [4.27–10.0].</td><td>0.000</td></tr><tr><td>Age at diagnosis</td><td>1.04 [1.03–1.06]</td><td>0.003</td></tr><tr><td>R0 resection (final)</td><td>0.22 [0.10–0.49]</td><td>0.055</td></tr><tr><td><strong>Progression free survival</strong></td><td></td><td></td></tr><tr><td>SEF</td><td>2.65 [2.09–3.37]</td><td>0.000</td></tr><tr><td>Size > 5 cm</td><td>1.87 [1.45–2.41]</td><td>0.012</td></tr><tr><td>R0 resection (final)</td><td>0.47 [0.34–0.57]</td><td>0.001</td></tr><tr><td><strong>LGFMS</strong></td><td></td><td></td></tr><tr><td><strong>Overall survival</strong></td><td></td><td></td></tr><tr><td>Age at diagnosis</td><td>1.09 [1.06–1.11]</td><td>0.000</td></tr><tr><td>Metastases at diagnosis</td><td>21.2 [11.2–40.4].</td><td>0.000</td></tr><tr><td><strong>Progression free survival</strong></td><td></td><td></td></tr><tr><td>Size > 5 cm</td><td>2.77 [1.94–3.94]</td><td>0.004</td></tr><tr><td>R0 resection (final)</td><td>0.47 [0.33–0.66]</td><td>0.027</td></tr><tr><td>Surgery in ref centers</td><td>0.52 [0.37–0.73]</td><td>0.055</td></tr><tr><td><strong>SEF</strong></td><td></td><td></td></tr><tr><td><strong>Overall survival</strong></td><td></td><td></td></tr><tr><td>Metastases at diagnosis</td><td>8.00. [4.03.– 15.9].</td><td>0.002</td></tr><tr><td><strong>Progression free survival</strong></td><td></td><td></td></tr><tr><td>R0 resection (final)</td><td>0.45 [0.28–0.68]</td><td>0.055</td></tr></tbody></table>

*: The following variables were included in the model: age (continuous), sex, tumor sites (internal trunk, trunk wall, upper & lower limbs, head and neck etc), depth, presence metastases at diagnosis, tumor spillage at first surgery, SEF vs LGFMS. quality of surgery (final, after reexcision if applicable) R0, R2, surgery in expert centers.

<table><caption>**Table 3**
Treatment proposed to patients treated in NETSARC centers.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">N (%)</th><th colspan="2">Time to next treatment Months (Median, range)</th></tr><tr><th>SEF</th><th>LGFMS</th></tr></thead><tbody><tr><td><strong>Medications</strong></td><td></td><td></td><td></td></tr><tr><td>Doxorubicin</td><td>12</td><td>13.2 (1.4–55.5)</td><td>11.2 (1.73–134.8)</td></tr><tr><td>Antiangiogenics</td><td>11</td><td>6.3 (0.53–27.0)</td><td>20.8 (7.2–28.0)</td></tr><tr><td>Trabectedin</td><td>6</td><td>8.4 (1.4–15.6)</td><td>2.8 (2.0–3.8)</td></tr><tr><td>Others</td><td>9</td><td>3.2 (1.6–6.7)</td><td>3.4 (3.4–3.6)</td></tr><tr><td><strong>Lines of treatment</strong></td><td></td><td></td><td></td></tr><tr><td>1</td><td>12</td><td>12.2 (1.4–55.3)</td><td>5.3 (1.7–134.8)</td></tr><tr><td>2</td><td>9</td><td>12.4 (1.6–22.0)</td><td>17 (2.0–20.8)</td></tr><tr><td>&gt;=3</td><td>18</td><td>4.1 (0.5–27.0)</td><td>5.5 (3.4–28.0)</td></tr></tbody></table>

* : others= trabectedine, paclitaxel, interferon alpha

independent favorable prognostic factors, while for SEF, only the R0 quality of resection retained an independent prognostic value.

In multivariate analysis for OS, age, tumor size, M1 at diagnosis independently correlated to survival. For the LGFMS subtype, only age and M1 at diagnosis were independent unfavorable prognostic factors, while for SEF, only M1 at diagnosis retained an independent prognostic value.

### 3.4. Medical treatment

116 of the 330 patients were treated from the initial diagnosis in one of the NETSARC reference centers and had a documented description of systemic treatments and outcome in the Conticabase. Twelve patients were reported to have received 40 different lines of treatment for a median number of lines of 3 (range 1–7). Doxorubicin, antiangiogenics (pazopanib or regorafenib), trabectedin, and others were given in 14, 11, 6, and 5 patients respectively. Four (10%) objective responses were observed, 3 in 7 (43%) SEF including 2/7 (29%) in first line with doxorubicin. There was one reported response in 6 (17%) LGFMS in first line with doxorubicin. Stable disease (SD) was reported as best response for 19 of the 40 lines of treatment (47.5%). Table 3 shows the median time to next treatment in SEF and LGFMS. The longest efficacy was reported with doxorubicin and antiangiogenics, as well as with trabectedin for SEF (Table 3).

### 4. Discussion

To the best of our knowledge, this is the largest series reporting the clinical presentation and outcome of patients with LGFMS and SEF, two ultrarare sarcomas, for which only limited information is available on their natural history. These two sarcomas share common histological and immunohistochemistry characteristics and occasionally present with similar molecular alterations, involving either the FUS or EWSR1 genes, with either CREB3L1 or CREB3L2 partners. The published literature, mostly retrospective, suggests however different natural histories, with a more aggressive behavior of SEF [7,8,12,13,17,19].

Our results show that LGFMS and SEF are indeed quite different diseases.

The clinical presentations of the two diseases are different, SEF presenting at a later age, with larger tumors, and a large proportion of metastatic lesions at diagnosis. The high rate of metastatic disease at diagnosis is observed even for small tumors and tumors occurring at a younger age (not shown). Also, the site of the primary tumor is more frequently the trunk in SEF.

Both SEF and LGFMS are associated with an important risk of relapse in the long term, despite a favorable outcome in the first five years. However, in patients in advanced phase, either at diagnosis or after relapse, PFS and OS in this series are longer in both SEF and LGFMS compared to other advanced ST sarcomas.

Despite sharing close or similar translocations as molecular drivers, the two tumors represent therefore different diseases, less aggressive for LGFMS bearing FUS translocations than SEF bearing EWSR1 translocations. Whether the observed clinical differences reflect differences in the transcriptomic targets of the fusion proteins and/or differences in the cell of origin of both diseases will be the subject of additional translational studies on this cohort. However, both are life-threatening diseases in the long term, sometimes decades after the initial diagnosis.

These two sarcomas have a considerable risk of relapse in the long term. This must be noted considering that LGFMS is diagnosed in children in 10% of the cases as well as young adults. The median age at diagnosis is in the fifth decade in this series. This worse than expected outcome must be noted while LGFMS has maybe a too good reputation in the first 5 years of follow-up. The overall prognosis of LGFMS is poor with late relapse causing late deaths from the disease.

As for other sarcomas, the R0 quality of initial surgery was found to be the critical prognostic factor for long-term survival [30,32,33]. As described before, surgery in sarcoma reference centers is also associated with a better outcome [30–35]. An intriguing observation was that the rate of R0 surgery was significantly lower in SEF, even in reference centers, and even after re-excision. This points to a different local and distant progression pattern of SEF with more infiltrative and locally invasive pattern. This is also supported by the observation that R0 surgery is associated with a less favorable long-term outcome in SEF as compared to LGFMS, with a higher proportion of local and distant relapses.

In this series, both SEF and LGFMS were found to have a longer PFS and OS in advanced phase as compared to other sarcomas in the NETSARC database, and as generally reported. While expected considering the low grade nature of LGFMS, this is more surprising for SEF reported to be a more aggressive tumor with higher risk of progression [17]. These two different fusion-positive sarcomas have therefore a more similar behavior in advanced phase than in localized phase.

Limited information is available concerning the activity of cytotoxic treatments and antiangiogenics in advanced LGFMS and SEF. Chamberlain et al and Chew et al reported on a limited activity of all cytotoxic agents assessed in single center study with a comparatively large but still limited number of patients reported [28,29]. The present study adds information to this limited body of knowledge, showing a detectable antitumor activity of doxorubicin in first line treatment in the two subtypes, and possibly a better antitumor- and sometimes very prolonged- activity of antiangiogenics in LGFMS, while trabectedin was
associated with a better PFS in SEF. These retrospective data with a
limited number of patients and should be considered with level of evi-
dence 5 in clinical practice guidelines [32,33]. Cytotoxic treatment can
show some level of activity in LGFMS and SEF, but prospective studies
are needed to determine their exact utility for these patients.

This study has several limitations. Limited information is available
on molecular subtypes (yet), the follow-up remains short, and the
quality of local and systemic treatments is not fully documented in a
proportion of patients. It provides however a benchmark for future
studies, in particular evaluating novel therapeutic approaches, and
could represent a source for synthetic control arms in these ultrarare
tumors where a randomized trial is not feasible [2,34], and where his-
torical control series provide the most relevant information for control
studies. With the ERN EURACAN, the Tracking study (https://clinicaltr-
ials.gov/ct2/show/NCT04921553) enables to collect information on the
response to systemic treatments.

In conclusion, LGFMS and SEF, while sharing close hallmark mo-
lecular alterations, have a very different clinical presentation, natural
history, and therapeutic outcome. They are not indolent diseases in the
long term, and should be rigorously managed at diagnosis, following
guidelines for sarcomas. Diagnostic and therapeutic management must
be conducted in sarcoma reference centers. A limited yet detectable
activity of systemic treatments is observed in some patients. These data
will also be of interest to be merged in larger international cohorts,
possibly using federated learning such as in the the Starter program
(https://euracan.eu/registries/starter/), to comply with data protection
regulation, to refine these observations.

Ethical approval

These databases and the work on these databases were approved by
the French Ethic Committee and Agency in charge of non-interventional
trials: the “Comité Consultatif sur le Traitement de l’Information en
matière de Recherche dans le domaine de la Sante (CCTIRS: number of
approval 09.594)” and the “Commission Nationale Informatique et Lib-
erte (CNIL: number of approval 909510)”.

Funding

NetSARC (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS) and LYRICAN+ (INCa-DGOS-INSERM-ITMO cancer_18003), LabEx DEvweCAN (ANR-10-LABX-0061), Eurosarc (FP7-278742), EURACAN (EC 739521), La Ligue contre le Cancer, Association DAM's, la Fondation ARC, Infosarcome, InterSARC (INCA), Ligue de L'Ain contre le Cancer, funded the study. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

CRediT authorship contribution statement

J-YB, NP, ALC included patients, conceived the study, contributed to the analysis, prepared the first draft and approved the final version. CT, MT, AI, MR, EB, TV, FD, LRLN, SW, NF, PDL, MRo, CP, AH, CL, ES-B, PS, FF, FB, PB, GV, SB, CH, P M-B, VM, MC, DB, PM, AB, VD, SC, MF, GD, FG, AD, MB included patients, reviewed the draft version of the article and approved the final version. CN, FLL, MK, AM, reviewed pathological diagnosis, reviewed the draft version of the article and approved the final version. CC-A, FD provided database extraction and analysis, and administrative support.

Declaration of Competing Interest

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.

Data availability

Patients did not provide consent for sharing of their information
outside the network but reasonable request for access to the database
can be granted on one of the Netsar.c site.

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