Objective High grade endometrial stromal sarcoma and undifferentiated uterine sarcomas are associated with a very poor prognosis. Although large surgical resection is the standard of care, the optimal adjuvant strategy remains unclear.
Methods A retrospective analysis of patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas (stages I–III) treated in 10 French Sarcoma Group centers was conducted.
Results 39 patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas treated from 2008 to 2016 were included. 24/39 patients (61.5%) were stage I at diagnosis. 38/39 patients underwent surgical resection, with total hysterectomy and bilateral oophorectomy completed in 26/38 (68%). Surgeries were mostly resection complete (R0, 23/38, 60%) and microscopically incomplete resection (R1, 6/38, 16%). 22 patients (58%) underwent postoperative radiotherapy (including brachytherapy in 11 cases), and 11 (29%) underwent adjuvant chemotherapy. After a median follow-up of 33 months (range 2.6–112), 17/39 patients were alive and 21/39 (54%) had relapsed (9 local relapses and 16 metastases). The 3 year and 5 year overall survival rates were 49.8% and 31.1%, respectively, and 3 year and 5 year disease free survival rates were 42.7% and 16.0%, respectively. Median overall survival and disease free survival were 32.7 (95% CI 16.3–49.1) and 23 (4.4–41.6) months, respectively. Medians were, respectively, 46.7 months and 39.0 months among those who underwent adjuvant radiotherapy and 41.0 months and 10.3 months for those who underwent adjuvant chemotherapy. In multivariate analysis, adjuvant radiotherapy was an independent prognostic factor for overall survival (P=0.012) and disease free survival (P=0.036). Chemotherapy, International Federation of Gynecology and Obstetrics I–II stages, and Eastern Cooperative Oncology Group-performance status 0 correlated with improved overall survival (P=0.034, P=0.002, P=0.006), and absence of vascular invasion (P=0.014) was associated with better disease free survival.
Conclusions The standard treatment of primary localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas is total hysterectomy and bilateral oophorectomy. The current study shows that adjuvant radiotherapy and adjuvant chemotherapy appear to improve overall survival. A prospective large study is warranted to validate this therapeutic management.
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This is the largest series of localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas.
Standard treatment for this patient population is radical hysterectomy and bilateral oophorectomy.
Adjuvant radiotherapy and adjuvant chemotherapy appear to be beneficial for overall survival.
Uterine sarcomas are rare and often involve an aggressive clinical course. Clinical studies are few and typically include a broad range of histological subtypes of uterine sarcoma, limiting interpretation, and clinical application.1 Endometrial stromal sarcomas are the most rare uterine malignancies, accounting for <2% of all uterine tumors and approximately 25– to 30% of all uterine sarcomas.2
According to the 2014 World Health Organization (WHO) classification, endometrial stroma tumors are classified into four categories: benign endometrial nodule, low grade endometrial stromal sarcoma, high grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma.3 Undifferentiated uterine sarcomas are the least frequent of the four pathological endometrial stromal sarcoma types.4 The YWHAE-FAM22 translocation identifies high grade endometrial stromal sarcoma while undifferentiated uterine sarcoma exhibits no specific translocation pattern. High grade endometrial stromal sarcoma and undifferentiated uterine sarcoma have a poor prognosis with a 5 year survival rate of approximately 25–30%.4–10 Considering the low incidence, evidence about management of localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma is limited.
The three largest published series included only 30, 21, and 13 patients, respectively, and patients had both localized and metastatic disease (stage IV International Federation of Gynecology and Obstetrics (FIGO) classification).11–13 Conventional management of localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma typically includes total hysterectomy and bilateral salpingo-oophorectmy. The role of lymphadenectomy and debulking of gross extrauterine disease remains unclear.14 15 Although radiotherapy and chemotherapy are considered adjuvant treatment, few data have been reported on their effectiveness.1 13 16
The aim of the present study was to evaluate the characteristics and clinical outcomes of a series of 39 patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma treated in reference sarcoma centers, all members of the French Sarcoma Group, over a 9 year period, and to provide information on tumor characteristics, disease diagnosis and stage, multimodal therapeutic modalities, outcome, and survival.
Materials and Methods
Patients were identified from two French sarcoma databases: NetSarc, the French clinical reference network for soft tissue and visceral sarcomas; and RRePS, the French sarcoma pathological reference network. NetSarc centrally reviews pathology and collects clinical information on treatment as well as outcomes for all sarcoma patients treated at one of 26 French oncology centers. RRePS includes all certified centers for pathological management of soft tissue sarcomas and viscera.
In the current study, the clinical data of adult patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma (with FIGO (online supplementary Appendix 1,17) stages I, II, and III only) treated between January 2008 and January 2017 in 10 NetSarc centers were prospectively registered in the two above mentioned databases, and patient medical records were retrospectively reviewed. Additional information collected included clinical history and symptoms, diagnostic modalities (gynecological examination, computed tomography (CT) scan, magnetic resonance imaging (MRI)), tumor characteristics, treatment approaches, including quality of surgical management (R0, resection complete; R1, microscopically incomplete resection; R2, macroscopically incomplete resection), type of adjuvant treatment (pelvic radiotherapy and/or chemotherapy), and outcome (relapse and type of relapse). The diagnosis of high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma was confirmed by a local pathologist of the RRePS network. Only patients with a diagnosis of high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by a pathologist with expertise in sarcomas were included. If the tumor was found to have invaded the bladder and/or the rectum, and/or there were distant metastases (stage IV)17 discovered preoperatively or immediately postoperatively, patients were not included in the study. Follow-up information was obtained during postoperative follow-up visits.18
All data were anonymized, and the database was closed in January 2017. Data were subjected to a descriptive analysis, with numbers and percentages for qualitative variables, and mean (SD) or median (range) values for quantitative variables. Survival curves were plotted using the Kaplan–Meier method and compared with the log rank test. Multivariate Cox regression models were then used. Adjuvant treatments were systematically included in the models. All variables statistically significant in univariate analysis (log rank test P<0.05) were considered in the multivariate models. Only variables which remained associated with a P value <0.05 were kept in the models. Overall survival was calculated based on the interval from diagnosis to patient death or last follow-up. Disease free survival was defined as the interval between diagnosis and local relapse and/or distant metastasis. All statistical tests were two sided, and the threshold for statistical significance was set at P=0.05. Analyses were performed with IBM SPSS Statistics 20 software (IBM Inc, New York, USA).
Thirty-nine adult patients presented between January 2008 and January 2017 with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma (FIGO stage I, II, and III) and were included in this series. Patients and tumor characteristics are reported in Table 1.
Seventy-seven per cent of patients were categorized as Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0–1% and 61.5% with FIGO stage I disease.
Initial imaging evaluation involved preoperative abdominal and pelvic CT scan and pelvic MRI in 38.5% and 74% of patients, respectively. Seventeen patients (43.6%) underwent preoperative chest imaging, 15 patients (38.5%) underwent chest imaging postoperatively, and imaging time was not specified for 7 patients (17.9%). Only 15 patients (38.5%) underwent preoperative endometrial biopsy or dilation and curettage; a diagnosis was made postoperatively after total hysterectomy for all other patients (n=24; 61.5%). Mutational status was identified for 7 of the 16 patients analyzed (44%). Among the 7, there were 5 YWHAE-FAM22 translocations, 1 mutation of the JAZF1 gene, and 1 mutation of the RB1 gene. Mutational status did not provide prognostic values given the large number of data gaps (23 patients did not have mutation status identified).
Treatment modalities and outcomes are reported in Table 2.
Thirty-eight patients underwent surgery; owing to locally advanced disease progression (FIGO IIIA), one patient underwent neoadjuvant chemotherapy with doxorubicin and ifosfamide and no primary tumor resection. Twenty-six patients (68.4%) underwent complete resection of localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma (total hysterectomy and bilateral oophorectomy).
Of the patients who underwent surgery, 38 (100%) underwent total hysterectomy, 26 (68.4%) bilateral oophorectomy, 9 (23.7%) pelvic lymphadenectomy, and 3 (7.9%) pre-aortic lymphadnectomy.
Adjuvant treatment was determined for 33/38 patients (87%) at a multidisciplinary committee, 32 (84.2%) of whom underwent postoperative adjuvant therapy and 1 patient died before being able to benefit.
Twenty-two patients (58%) underwent pelvic radiation with a delivered dose range of 45.0–50.4 Gy. Brachytherapy, when used, was always associated with pelvic radiation therapy. Eleven patients (29%) underwent various regimens of adjuvant chemotherapy (four adriamycin–cisplatin–ifosfamide, four adriamycin–ifosfamide, one carboplatin–paclitaxel, and two unknowns), with a median number of four delivered cycles. Five patients received both adjuvant radiotherapy of the pelvis and chemotherapy.
There was a non-significant association between radiotherapy and FIGO stage. Radiotherapy was administered to 68.2% of patients with FIGO stage 1, 66.7% of patients with FIGO stage 2, and 28.6% of patients with FIGO stage 3 disease (P=0.158). There was a significant association between chemotherapy and FIGO stage: chemotherapy was administered to 22.7% of patients with FIGO stage 1, 0% of patients with FIGO stage 2, and 71.4% of patients with FIGO stage 3 disease (P=0.043).
After a median follow-up time of 33 months (range 2.6–112 months), 21 patients (54%) had recurrence following primary tumor resection, 5 patients (13%) developed a local relapse and distant metastases, 11 patients (29%) developed distant metastases only, and 4 patients (10%) developed local relapse only (for 1 patient the site of relapse was unknown). Common metastatic sites were the lungs (11.8%), peritoneum (7.5%), lymph nodes (4.3%), and bones (3%). The disease free survival rates at 3 and 5 years were 42.7% and 16%, respectively. Median disease free survival was 23 months (95% CI 4.4–41.6 months). Twenty-two (56.4%) patients died during the follow-up period. The overall survival rates at 3 and 5 years were 49.8% and 31.0%, respectively. Median overall survival was 32.7 months (95% CI 16.3–49.1 months) (Table 3, and see online supplementary Appendix 2).
According to univariate analysis, only vascular emboli were significantly predictive of disease free survival (P=0.024). Adjuvant radiotherapy, although not significant (P=0.058), appeared to be beneficial for patients in terms of disease free survival. Of the 22 patients who underwent radiation, 4 (18%) recurred locally; 3/14 non-irradiated patients (21.5%) recurred locally. Regarding overall survival, significant prognostic factors included FIGO stage (I–II vs III, P<0.0001), quality of tumor resection (R0–R1 vs R2, P=0.027), ECOG-PS (0 vs 1–2, P=0.02), and adjuvant radiotherapy (P<0.0001). The mitotic index and administration of adjuvant chemotherapy were not prognostic for disease free survival or overall survival. Nevertheless, among the 11 patients who received adjuvant chemotherapy, 4 (36%) developed distant metastases compared with 13/24 (54%) patients who did not receive adjuvant chemotherapy (local disease for 3 patients, metastases for 8, both for 3). Prognostic factors are shown in Figure 1, and in the online supplementary Appendices 3 and 4.
Multivariate analysis showed that adjuvant radiotherapy was an independent prognostic factor for overall survival (P=0.012) and disease free survival (P=0.036). Overall survival was significantly associated with treatment with adjuvant chemotherapy (P=0.034, compared with no treatment), FIGO stage (P=0.002, I–II vs III), and ECOG-PS (P=0.006, 0 vs 1–2). Disease free survival was significantly associated with vascular invasion (P=0.014).
Chemotherapy, FIGO stage I–II, and ECOG-PS 0 correlated with improved overall survival (P=0.034, P=0.002, P=0.006, respectively); absence of vascular invasion (P=0.014) was associated with better disease free survival. The results of the multivariate analysis are shown in Table 4.
High grade endometrial stromal sarcoma and undifferentiated uterine sarcoma are rare aggressive uterine mesenchymal tumors and infrequently reported in the literature. To our knowledge, only four series have reported more than 10 patients,11–13 19 but with confounding localized and metastatic disease. The remaining isolated reports are usually described as case reports. The current study is a retrospective analysis of 39 patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma, treated over 9 years, based on the experience of 10 centers and histological diagnoses by an expert sarcoma pathologist. This is the largest series reporting the mode of diagnosis as well as surgical and treatment outcomes. Interestingly, in the current series, 43.6% of patients had no initial preoperative chest imaging assessment and 74% had pelvic MRI preoperatively. Histological diagnosis was known before surgery in 20% of patients following ultrasound guided endometrial biopsy. For all other patients, the sarcoma was diagnosed via operative pathology (after dilation and curettage for some or after total hysterectomy for the vast majority).
Surprisingly, the majority of patients (61.5%) had FIGO stage 1 disease compared with reports by Malouf et al, Tanner et al, and Schick et al11 12 19 of 20%, 33%, and 34% of patients with FIGO stage 1 disease, respectively.
Total en bloc hysterectomy and bilateral oophorectomy is the standard recommended surgical treatment for localized high grade endometrial stromal sarcoma/undifferentiated uterine sarcoma.11 12 14 20 21 In the current study, surgical resection was complete (total hysterectomy and bilateral oophorectomy) for 68% of patients and incomplete for 32%, and surgery was performed by laparotomy in 84% of patients. Tumor rupture or tumor morcellation were infrequent (16%). Pelvic and/or pre-aortic lymphadenectomy was not useful when there was a lack of macroscopic involvement, in agreement with the 2014 European Society for Medical Oncology and Gynecologic Cancer Intergroup guidelines.15 22–24
More than 80% of patients in the current series received adjuvant treatment; 58% of patients received postoperative pelvic radiotherapy, associated with brachytherapy in 30% of cases. This is similar to the series by Tanner et al12 where 5 of 7 patients with stage I disease received adjuvant therapy (4 radiotherapy and 1 chemotherapy), 8 of 10 patients with localized high grade endometrial stromal sarcoma/undifferentiated uterine sarcoma stages I and II resected disease received postoperative radiotherapy in the series by Rios et al,13 and 4 of 8 patients in the series by Malouf et al11 received postoperative radiotherapy. To date, external pelvic irradiation has been widely used as adjuvant treatment for uterine sarcomas, as it has been reported to decrease local recurrence.4 25 The European Society for Medical Oncology guidelines note that adjuvant radiotherapy may be an option in select cases after shared decision making with the patient and a multidisciplinary team, taking into account special risk factors such as cervical involvement, parametral involvement, serosal involvement and high grade endometrial stromal sarcoma/undifferentiated uterine sarcoma histology. In the current series, pelvic radiotherapy with or without brachytherapy was identified as an independent prognostic factor significantly associated with longer overall survival and disease free survival, as in the series by Malouf et al and Shick et al.11 19 Nevertheless, these results should be evaluated with caution. On the one hand, there is a limited number of patients who have been studied, and on the other hand, the study period of 9 years for the current series and more than 20 years for the series by Malouf et al11 and Schick et al 19 is substantial. The statistical power is low in all three studies, given the size of the cohorts (20, 30, and 39 patients in the series by Malouf et al,11 Schick et al,19 and the current study, respectively). The EORTC 55874 randomized trial included all uterine sarcoma types, and did not show any overall survival or disease free survival benefit from adjuvant radiotherapy in patients with stage I or II resected uterine sarcoma.26 It did reduce local recurrence for patients with carcinosarcoma only.
Almost 29% of patients underwent adjuvant chemotherapy in the current series, higher than what has been reported in previously published series (3 of 10 patients with resected FIGO stages I and II received adjuvant chemotherapy in the series by Rios et al,13 1 of 9 patients received adjuvant chemotherapy in the series by Maalouf et al,11 12 of 29 patients with resected FIGO stages I, II, and III received adjuvant chemotherapy in the series by Schick et al,19 and 1 of 7 patients with stage I resected disease received adjuvant chemotherapy in the series by Tanner et al). In the current series, adjuvant chemotherapy was identified as an independent prognostic factor significantly associated with longer overall survival, but these results should be considered with caution owing to the limited number. Currently, there is still no definitive evidence supporting the role of adjuvant chemotherapy in patients with high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma.22 The randomized trial by the Gynecologic Oncology Group compared adjuvant chemotherapy using doxorubicin with no postoperative treatment in 156 patients with stage I or II uterine sarcoma, of all histological subtypes, including a cohort of 12 high grade endometrial stromal sarcoma/undifferentiated uterine sarcoma.27 The study did not demonstrate the benefit of adjuvant chemotherapy. Nevertheless, the randomized study by SARCGYN,28 involving 81 patients with localized uterine sarcomas (including 9 undifferentiated uterine sarcomas), who were randomly allocated to receive either adjuvant chemotherapy (with doxorubicin, ifosfamide, and cisplatin) followed by pelvic radiotherapy or pelvic radiotherapy alone, showed that combined chemotherapy and radiotherapy increased the 3 year disease free survival rate significantly versus radiotherapy alone (55% vs 41%, P=0.048), but with a non-significant improvement in overall survival at 3 years (81% vs 69%). Consistent with previous series, the median overall survival of patients in the current series was better (median 32.7 months (95% CI 16.3 to 49.1)), but included only 23% of patients with FIGO stage III disease and no stage IV. In the literature, patients typically present with advanced disease, as in the series by Tanner et al12 and Malouf et al,11 with 52% and 62% of patients with FIGO stage IV disease, respectively, and a median overallsurvival of 11.8 months and 23 months, respectively. In the current series, after a median follow-up of 33 months, 21 (54%) patients with resected tumor recurred, mainly with distant metastases (n=16, 41%) and some with local relapse (n=9, 23%), and a median relapse time of 23 months. This median relapse time is longer than in other series (12 months in the series by Schick et al,19 9 months in the series by Malouf et al11). Adjuvant treatment may have played a role in postponing relapses if more patients had been treated with adjuvant chemotherapy and/or radiotherapy.
Given the recent modification of the classification of endometrial stromal tumors29 and the previous inclusion of our patients (from 2008), many patients have not benefited from research of the YWHAE-FAM22 translocation to differentiate high grade endometrial stromal sarcoma from undifferentiated uterine sarcoma but these two entities remain the most aggressive of endometrial stroma sarcomas.
Interestingly, Hardell et al10 recently demonstrated the prognostic value of mitotic index cut-off (of 25 mitoses/10 high power fields) in undifferentiated uterine sarcoma in an independent cohort of 40 patients with undifferentiated uterine sarcoma. The authors propose that undifferentiated uterine sarcoma should be divided by mitotic index into 'mitogenic' and 'NOS' (ie, tumors with mitotic index below the cut-off). Their study reaffirms that a subgroup of patients with 'NOS' undifferentiated uterine sarcoma can achieve long term survival and that better methods of determining prognosis are needed.10 Mitotic index was not a prognostic factor in the current series.
Undifferentiated uterine sarcoma is challenging to treat owing to the rarity of the disease, the difficulty of establishing the histological diagnosis, and the high risk of recurrence, and should thus be evaluated in specialized sarcoma treatment centers.
Adjuvant chemotherapy had a significant impact on overallsurvival in the current series and thus we recommend that treatment be considered as part of the therapeutic strategy for patients with high grade endometrial stromal sarcoma/undifferentiated uterine sarcoma by a multidisciplinary team because of the high incidence of distant metastases. A prospective large study is warranted to validate this therapeutic management.
Contributors JM performed the statistical analysis. The other authors contributed to the recovery of patient data on the various French sites. FD supervised the study.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Ethics approval The registry was approved by the INCa (Institut National du Cancer) and local authorities (CNIL). RRePS and NETSARC databases are approved by the French Ethics Committee and National Agency CCTIRS (approval#09.594) and National Commission on Computing and Freedom (CNIL Approval # 90951018). The current study was a retrospective, minimal risk study, and all patients provided informed consented for use of their clinical data. Our institutional review board exempts such studies from requiring approval, and the FSG board of directors approved the study.
Provenance and peer review Not commissioned; externally peer reviewed.