Article Evaluation of treatment strategies and prognostic factors of 135 patients with low-grade endometrial stromal sarcoma

Background: To evaluate the influence of treatment modalities and prognostic factors on the survival of patients with low-grade endometrial stromal sarcoma (LGESS). Methods: One hundred and thirty-five LGESS patients in Fudan University Shanghai Cancer Center from January 2006 to December 2018 were retrospectively reviewed. Results: Two patients received fertility-sparing surgery while 133 patients received hysterectomy. The median follow-up duration was 52 months (3–342 months). One hundred and nine (80.7%) patients received ovariectomy, 73 (54.1%) patients had lymphadenectomy, 83 (61.5%) patients received adjuvant therapy. The 5-year and 10-year disease free survival rates were 72.0% and 61.0%, respectively. The 5-year and 10-year overall survival rates were 88.0% and 79.8%, respectively. Surgery for recurrence was associated with improved overall survival although the complication rate was about 27.6%. Multivariate analysis showed that lymphovascular invasion was associated with disease free survival (hazard ratio, 0.473; 95 % confidence interval, 0.235–0.952; p=0.036) and menopausal status was related to overall survival (hazard ratio, 5.561; 95 % confidence interval, 1.400–22.084; p=0.015). Conclusions: There was no effect of lymphadenectomy, ovariectomy, or adjuvant therapy on patients’ recurrence and survival. Hysterectomy may be proposed as the standard treatment for LGESS. Surgery for replase was an acceptable method to improve overall survival. Lymphovascular invasion was a significant independent factor for disease free survival. Postmenopause was the poor prognostic factor for overall survival.

interval, 1.400-22.084; p=0.015). Conclusions: There was no effect of lymphadenectomy, ovariectomy, or adjuvant therapy on patients' recurrence and survival. Hysterectomy may be proposed as the standard treatment for LGESS. Surgery for replase was an acceptable method to improve overall survival. Lymphovascular invasion was a significant independent factor for disease free survival. Postmenopause was the poor prognostic factor for overall survival.

Background
Endometrial stromal sarcoma (ESS) is a relatively rare tumor that accounts for approximately 0.2% of uterine malignancies, 20% of uterine sarcomas [1] LGESS is the most common type of ESS, and hysterectomy is regarded as the main treatment [5].
However, the roles of other therapies such as ovarian preservation, lymphadenectomy, and adjuvant therapy, remain controversial. Because of universal expression of estrogen and progesterone 3 receptors [6], bilateral salpingo-oophorectomy (BSO), or hormone therapy, or both together, were postulated. The value of hormone therapy for early-stage ESS remains unproven [7]. LGESS is defined by a low mitotic index, and so is considered to be insensitive to chemotherapy. Radiation was not associated with increased survival for LGESS [8]. The effect of lymphadenectomy was also uncertain. For patients with adjuvant radiotherapy, the radiation treatment included external pelvic irradiation (18 MV X-rays) with one fraction of 1.8-2.0 Gy daily for a total dose of 50 Gy in 5-6 weeks.
Chemotherapy was generally done in 3-6 cycles over a 3-week period. 4 The relevant factors in the medical records were listed: age, menopausal status, patient's symptom, laparoscopic myomectomy, tumor size, muscular infiltration, lymphovascular invasion, lymph node metastasis, FIGO stage, lymphadenectomy, ovariectomy, adjuvant therapy, residual disease, and recurrence. The diagnosis for each case was based on surgical pathology. When the recurrence was

Clinicopathologic factors and treatment strategies of LEGSS patients
Of 153 ESS during the study period, 135 (88.2%) patients were identified as LGESS while 15 (9.8%) HGESS and 3 (2.0%) UUS patients were excluded in the analysis.

Survival and recurrence
The patients were followed up for a median duration of 52 months (3-342 months). The 5-year and 10-year disease free survival rates were 72.0% and 61.0%, respectively (Fig. 1A).

Treatment modalities and clinicopathologic factors associated with disease free survival or overall survival
In univariate analyses for disease free survival, menopausal status was associated with disease free 6 survival (p<0.05). So were deep muscle infiltration (p<0.05) and lymphovascular invasion (p<0.01).
When we further assessed different treatment methods and prognotic factors in 108 LGESS patients with stage I, we still found the similar results (data not shown).

Discussion
Endometrial stromal sarcomas were rare uterine malignancies that might manifest through abnormal uterine bleeding (55.2%) and pelvic mass (28.1%) [1]. In our study, the majority (62.2%) of LGESS patients had no symptoms and the second symptom was abnormal vaginal bleeding in 37(27.4%) patients (Table 1). Because the preoperative diagnosis was ambiguous and the intraoperative frozen pathology had its limitation, almost all the patients were diagnosed postoperatively. Thus, 56 (41.5%) patients received a secondary operation after the first surgery was hysteromyoma or subtotal hysterectomy. Moreover, laparoscopy was often used in the first operation. Choo suggested that intrapelvic dissemination was due to electronic morcellation [9]. A consensus review suggested morcellation should be avoided [10]. However, we found the history of laparoscopic myomectomy was related to neighter overall survival nor disease free survival.
The mean age at diagnosis was 41.2 years (19-65 years) and 118 patients (87.4%) were premenopausal. Therefore, it was worth considering fertility-sparing surgery or ovarian preservation.
Zhou suggested that ovarian preservation had no significant effect on disease free survival and ovarian preservation was feasible [1]. It was also reported that fertility-sparing surgery may be considered for early-stage LGESS patients [11,12]. Rather, some study suggested that the removal of the adnexa might be helpful to decrease the risk of recurrence [13]. In our study, 2 patients received fertility-sparing surgery with adjuvant hormone therapy after operation and no recurrences occured yet. Moreover, our analysis showed that ovarian removal had no significant effect on disease free survival (p=0.443) and overall survival (p=0.854).
According to 2009 FIGO guidelines, initial complete staging for endometrial stromal sarcoma would need lymphadenectomy. Previous studies demostrated that the incidence of lymph node metastasis ranged from 16% to 33% [14,15]. In our study, 73 patients received lymphadenectomy and only 9 cases had lymph node metastases. Currently, the benefit of lymph node resection in LGESS is controversial. One meta-analysis suggest that lymphadenectomy bore little prognostic or therapeutic benefit in patients with uterine sarcoma [16]. However, another study showed total hysterectomy with BSO followed by pelvic lymphadenectomy was associated with an improved outcome [17]. Our data found that lymphadenectomy had no effect on both disease free survival (p=0.246) and overall survival (p=0.652). So, we did not advocate the integration of lymphadenectomy in LGESS.
The ability of adjuvant treatment in patients with uterine sarcomas was unclear and there was no standard recommendation regarding adjuvant therapy [18]. Schick found that adjuvant radiotherapy was an independent prognostic factor for overall survival [19]. Use of adjuvant chemotherapy and radiotherapy were reported to be associated with better prognosis only for HGESS [8,20]. Cade's study did not regard primary adjuvant progestogen as a survival benefit [21]. Our analyses showed that adjuvant therapy was not associated with disease free survival or overall survival.
The rucurrent rate increased with the development of the stage in our paper. The median time to recurrence was 24 months (1-321 months). Twenty-nine (74.4%) out of 39 recurrent LGESS patients received cytoredductive surgery. The surgery for recurrence was associated with improved overall survival although the complication rate was about 27.6%. Yamazaki also found that the post-relapse survival of patients with endometrial stromal sarcoma can be expected to be >10 years when treated by repeated surgical resection [22]. So repeated surgery for recurrent disease should be an acceptable method.
The 5-year relapse free survival and overall survival rates were 66.1% and 95.8% [23]. In our study, the 5-year disease free survival and overall survival rates were 72.0% and 88.0%. Khatib found that stage, age, lymphovascular invasion, and lymphadenectomy were independent prognostic factors for disease free survival and so was stage for overall survival [24]. Another paper showed that age, lymphadenectomy, stage I, and adjuvant therapy did not affect disease free survival or overall survival [25]. On multivariate analysis, only lymphovascular invasion was an independent predictor for disease free survival and so was menopausal status for overall survival in our research. So we suggested lymphovascular invasion was a high risk factor for recurrence and uterine tumors after menopause are well worth our attention.

Conclusions
In conclusion, lymphadenectomy, ovariectomy, or adjuvant therapy had no effect on survival in LGESS patients. Hysterectomy may be proposed as the standard treatment. Cytoreductive surgery for relapse could improve overall survival in recurrent cases. Lymphovascular invasion was a significant independent factor for disease free survival. Post-menopause was the poor prognostic factor for overall survival. We also found the similar results in LGESS patients with stage I.

Ethics approval and consent to participate
This study was conducted according to the declaration of Helsinki and was approved by the Committee of Fudan University Shanghai Cancer Center.

Consent for publication
Written informed consents were obtained from all individual participants included in the study.