Gynecologic Oncology 132 (2014) 654–660

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Gynecologic Oncology

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Ovary and uterus-sparing procedures for low-grade endometrial stromalsarcoma: A retrospective study of 153 cases☆,☆☆

Huimin Bai a, Jiaxin Yang a, Dongyan Cao a, Huifang Huang a, Yang Xiang a, MingWu a, Quancai Cui b, Jie Chen b,Jinghe Lang a, Keng Shen a,⁎a Department of Obstetrics and Gynecology, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Chinab Department of Pathology, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, China

H I G H L I G H T S

• Hysterectomy with bilateral salpingo-oophorectomy and complete resection of the macroscopic lesion should be treated as the mainstay treatments for LG-ESS.• Ovary-sparing procedures could be considered for young women without cervical involvement; however, long-term follow-up should be mandatory.• Myomectomy should only be conserved for young patients with a strong desire for future fertility, with fully informed consent.

☆ Source of the study: Peking Union Medical CollegeMedical Sciences & Peking Union Medical College (PUMC☆☆ Grant support: National Science and TechnologyNational Key Technologies R&D Program of China” (Grant

⁎ Corresponding author. Fax: +86 10 65212507.E-mail addresses: shenkeng@vip.sina.com, skpumch@

0090-8258/$ – see front matter © 2013 Elsevier Inc. All rihttp://dx.doi.org/10.1016/j.ygyno.2013.12.032

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 10 October 2013Accepted 23 December 2013Available online 9 January 2014

Keywords:Endometrial stromal sarcomaESSLow gradePrognosisRecurrenceTreatment

Objective. To discuss the optimal treatment options for low grade endometrial stromal sarcoma (LG-ESS).Methods. Medical records of consecutive patients with LG-ESS in our institute were collected. The pertinent

data, including clinicopathological characteristics, treatment and prognostic information were evaluated.Results. A total of 153 cases of LG-ESS were included. The 5-year relapse free survival (RFS), overall survival

(OS) and survival after relapse (SAR) rates were 66.1%, 95.8% and 82.9%, respectively. Ovary-sparing procedures,positive resection-margins, and myomectomy were the independent adverse factors for relapse (P b 0.0001, =0.0041, and =0.0075, respectively). Post-menopause, cervical involvement, and positive lymphovascular spaceinvolvement were significantly associatedwith survival (P b 0.0001, =0.0020, and=0.0163, respectively). Dis-tance recurrence and macroscopically residual tumors negatively affected SAR (P = 0.0137 and =0.0004, re-spectively). No benefit was found for lymphadenectomy in terms of both RFS and OS (P = 0.1187 and =0.5138, respectively). Initial ovary-sparing procedures and myomectomy had no impact on OS (P = 0.0810

and =0.8845, respectively). Adjuvant treatment had a slightly beneficial effect both on OS and SAR.

Conclusion. Hysterectomy with bilateral salpingo-oophorectomy and complete resection of the macroscopiclesion should be treated as the initial and salvagemainstay treatments for LG-ESS patients. Ovary-sparing proce-dures could be considered for young women without cervical involvement; however, long-term follow-upshould bemandatory. Myomectomy should only be conserved for young patients with a strong desire for futurefertility, with fully informed consent; hysterectomy was recommended after the completion of pregnancy anddelivery. However, the roles of lymphadenectomy and adjuvant treatment deserve further investigation.

© 2013 Elsevier Inc. All rights reserved.

Introduction

Endometrial stromal sarcoma (ESS) is a rare tumor that representsapproximately 7–15% of all uterine sarcomas but only 0.2% of all uterinemalignancies [1]. Based on the mitotic rate, ESS is histologically dividedinto two groups: high-grade (HG) and low-grade (LG) [2]. HG-ESS is

Hospital, Chinese Academy ofH).Infrastructure Program “The2008BAI57B02).

126.com (K. Shen).

ghts reserved.

currently defined as an undifferentiated endometrial sarcoma (UES),characterized by more than 10 mitoses per 10 high-power fields(HPFs). Additionally, this sarcoma is more aggressive and has a poorerprognosis. In contrast, LG-ESS has fewer than 10 mitoses per 10 HPFs,and the cell nuclei are not atypical or pleomorphic [2]. LG-ESS is rela-tivelymore common and tends to occur beforemenopause. LG-ESS usu-ally exhibits a more indolent clinical course, but has high relapsepotential [3]. These two distinct entities should be treated differently.

For LG-ESS, hysterectomy is the cornerstone of treatment. However,the role of a bilateral salpingo-oophorectomy (BSO), as well as lymph-adenectomy for complete surgical staging, is debated. Adjuvant treat-ment, including hormonal treatment, chemotherapy and radiotherapy,has also not been established. The absence of consensus on the optimal

655H. Bai et al. / Gynecologic Oncology 132 (2014) 654–660

management of this disease is due to its rarity and the heterogeneity ofpreviously published series, the majority of which included HG tumorsand other histologic subtypes of uterine sarcoma [4]. In the presentstudy, we focused exclusively on LG-ESS and compiled 153 cases thatwere treated at our center, representing one of the largest series thathas been published. Our experience inmanaging this uncommon condi-tion and a review of related literature will also be discussed.

Table 1Clinical profile of the 153 cases with LG-ESS.

Parameter Number of patient Percent (%)

Age at diagnosis, y (mean; range) 41.8; 15–79Menstruation statusPremenopause 136 88.9Postmenopause 17 11.1

PresentationMetrorrhagia 74 48.4Pelvic pain or pelvic pressure 18 11.8Rapid growth of leiomyoma 10 6.5None 47 30.7n.a.a 4 2.6

Preoppresumptive diagnosisAsymptomatic leiomyoma 109 71.2Adenomyosis 9 5.9ESS (LG or HG) 19 12.4Others 16 10.5

Primary surgeryMyomectomy 19 12.4Hysterectomy 134 87.6BSOa 109 71.2Lymphadenectomy 46 30.1

Adjacent treatmentHTa 55 35.9CTa 27 17.6RTa 33 21.6Observation 67 43.8

Follow-up (month; range) 74.2 (1–396)RelapseNo 104 68.0Yes 49 32.0

Current statusNEDa 129 84.3AWDa 15 9.8DODa 9 5.9

a n.a.: Data not available; BSO: bilateral salpingo-oophorectomy; HT: Hormonal treat-ment; CT: Chemotherapy; RT: Radiation treatment; NED: No evidence of disease; AWD:Alive with disease; DOD: Die of disease.

Patients and methods

The medical records of women with LG-ESS who were diagnosedand treated at Peking Union Medical College Hospital (PUMCH) werecollected. All consecutive patients who underwent surgery and hadcomplete pathology and operation reports were included in the study,whereas patients whowere lost to follow-up immediately after surgerywere excluded. Clinical data, including clinicopathological variables,treatment, and follow-up information, were then evaluated.

In our series, hysterectomy was the major surgical procedure.Ovary-sparing procedures and lymphadenectomies were generallyperformed, depending on the patient's age, their informed consent,the extent of disease, and the institutional practices at the time. Two in-dependent pathologists with extensive backgrounds in gynecologicalpathology reviewed all pathological slides according to the 2003 WHOClassification and were blinded to the patients' outcomes. The marginalstatus was interpreted as positive when sarcomawas found at themar-gins ofmyomectomy specimens or in the parametria, cervix or vagina ofhysterectomy specimens. Macroscopically residual tumor was definedas residual tumor greater than 2 cm in greatest diameter. Staging ofthe disease was retrospectively performed according to the 2009 FIGOstaging system. In cases of incomplete surgical staging, the stage wasassessed based on available pathologic findings, with unevaluatedareas considered as negative formetastatic lesions, and on the operativerecords [5].

Adjuvant treatment was performedwithout well-defined protocols.The decision to administer hormonal treatment, chemotherapy, or ra-diotherapy was based on the extent of disease, medical comorbidities,institutional practices, or the doctor's preference. For hormonal treat-ment, megestrol acetate (160 mg/d) or an anti-aromatase inhibitor(250 mg/d) was commonly administered for 6 months. Alternatively,3–4 monthly injections of GnRHa were used. The main adjuvant intra-venous chemotherapy regimens consisted of PEI (70 mg/m2 cisplatin,d1–3; 60 mg/m2 epirubicin, d1; 1.5 g/m2 ifosfamide, d1–3; 0.2 gmesna, 0, 4, or 8 h post-ifosfamide application, d1–3, q28 days), PAC(50 mg/m2 cisplatin; 50 mg/m2 adriamycin; 500 mg/m2 cyclophospha-mide, iv, q28 days), and VAC (2 mg vincristine; 75 mg/m2 adriamycin;1200 mg/m2 cyclophosphamide, iv, q28 days). In total, 3–6 chemother-apy cycleswere administered. Themain radiation typewas pelvic radio-therapy with or without a vaginal boost. Brachytherapy and whole-abdominal radiotherapy were also applied according to the site andextent of the patients' disease.

After the treatment completion, the women were followed-upmonthly in the first half of the year, every 3 months in the second halfof the year, and every 6 months thereafter. For women for whom regu-lar follow-up information was not available, an effort wasmade to con-tact these patients by telephone or letter to obtain this information.

Relapse was defined by clinical or imaging evidence and was con-firmed pathologically. Local relapse was defined as pelvic or vaginal re-currence, and distant relapse was defined as recurrence in extra-pelviclocations. Relapse-free survival (RFS) times were calculated as the peri-od between the date of initial surgery and the date of relapse; womenliving disease free at the time of their last visit were censored. OStimes were calculated in months from the date of initial surgery to thedate of patient death from the disease, and survival after relapse(SAR) was defined as the time from relapse to the date of patient diedfrom the disease or of the last follow-up; patients who died from

other conditions and survivors at the time of their last visit werecensored.

The study protocol was approved by the ethics committee atPUMCH, Beijing, China.

Statistical analysis

All statistical analyses were performed using SAS® Version 9.2 (SASInstitute, Cary, NC). All tests were 2 sided, and P b 0.05 was consideredstatistically significant. The Kaplan–Meier method was used to analyzethe relapse and survival rates. A log rank test was used to compare thedifferent survival curves. A Cox proportional hazards model was usedto assess all parameters that were found to be significant in univariateanalysis.

Results

Demographic characteristics and clinical presentation

From July 1979 toMay 2013, 196 consecutivewomenwith ESSweretreated at PUMCH. In total, 32 cases were diagnosed as UES and wereexcluded from this study. A total of 11 patients (6.7%) were lost tofollow-up immediately after surgery, 7 of whom preferred to continuetreatment at hospitals near their residences due to their economic con-ditions. For the other 4 patients, relevant datawere not available in theirrecords. All of these patients were excluded from the analysis. There-fore, 153 LG-ESS caseswere ultimately included. The clinicopathologicalcharacteristics and treatment profiles of these patients are reported inTables 1 and 2. The patients' mean age at initial diagnosis was41.8 ± 10.7 (range: 15–79) years, and 136 (89.5%) cases involved pre-menopausal women, including 22 (14.4%) non-nulliparous women. No

Table 2Pathological characteristics of the 153 cases with LG-ESS.

Parameter Number of patient Percent (%)

Tumor size (cm) (mean; range): 6.2 (0.3–18)≤5 cm 90 58.8N5 cm 63 41.2

Myometrial invasion0 87 56.9≤50% 37 24.2N50% 29 19.0

Cervical involvement+ 18 11.8− 135 88.2

Gross extrauterine disease+ 23 15.0− 130 85.0

LVSI+ 24 15.7− 129 84.3

Resection marginsClear 136 88.9Involved 17 11.1

Modified FIGO stageI 130 85.0II 13 8.5III 9 5.9IV 1 0.7

Table 3Risk factors related to relapse and survival.

Parameter Relapse P valuea P valueb DOD P valuea P valueb

+ − + −

Age at diagnose≤45 37 69 0.4865 3 103 0.0023N45 12 35 6 41

Menstruation statusPremenopause 41 95 0.2411 3 133 b0.0001 b0.0001Postmenopause 8 9 6 11

Uterine surgeryMyomectomy 15 4 b0.0001 0.0075 1 18 0.8845Hysterectomy 34 100 8 126

Lymphadenectomy+ 10 36 0.1187 1 45 0.5138− 39 68 8 99

BSO+ 17 92 b0.0001 b0.0001 7 102 0.0810− 32 12 2 42

Myometrial invasion≤50% 42 82 0.3784 5 119 0.0028N50% 7 22 4 25

Tumor size≤5 cm 28 63 0.1614 5 86 0.4257N5 cm 21 41 4 58

Cervical involvement+ 6 12 0.6763 4 14 0.0467 0.0020− 43 92 5 130

LVSI+ 7 17 0.8847 3 21 0.0137 0.0163− 42 87 6 123

Resection marginsClear 40 96 0.0174 0.0041 5 131 0.0006Involved 9 8 4 13

StageI + II 44 99 0.1062 6 137 0.0027III + IV 5 5 3 7

Postoperative treatmentHT 14 41 0.1062c 3 52 0.2963c

CT 9 18 0.1403c 1 26 0.9383c

RT 4 29 0.0050c 3 30 0.1026c

Observation 28 39 4 63

a Log rank test.b Cox proportional hazards model.c Comparing to observation group.

656 H. Bai et al. / Gynecologic Oncology 132 (2014) 654–660

patient received hormonal treatment at the time of diagnosis in ourstudy. Metrorrhagia was the most common presentation (48.4%),followed by pelvic pain or pressure in 11.8% of patients. The most com-mon pre-operative presumptive diagnosis was leiomyoma (71.2%).

Surgery and adjuvant treatment

All 153 patients underwent surgical resection at least once as amainstay initial treatment (Table 2). Myomectomies with ovary-sparing procedures were performed in 19 (12.4%) cases, due to the ad-olescent or very young age of the patients (3 patients) or to their path-ological misdiagnosis as having benign leiomyoma. Among theseindividuals, 8 women had a spontaneous pregnancy, and 5 had a cesar-ean delivery after initial surgery. Hysterectomy was performed in 134(87.6%) cases, including 23 cases involving a debulking procedure.Ovarian function was preserved in 44 (28.8%) patients who were ex-empt from postoperative radiotherapy. Moreover, initial lymphadenec-tomy was performed in 46 (30.1%) cases for complete disease staging.The mean number of removed lymph nodes (LNs) was 20.1 ± 9.0 perpatient (range: 4–63). Positive pelvic nodes were present in only 1(2.2%) case. Extra-uterine and intra-abdominal diseases were presentin 23 (15.0%) women. The sites of extra-uterine disease included theparametruim (12 cases), adnexa (9), Douglas' cul-de-sac (3),rectosigmoid colon (2), bladder (1), retroperitoneum (1), and LNs (1).In 3 cases, tumor thrombi infiltrating the pelvic veins were noted.After initial surgery, 17 (11.1%) patients had involved resectionmargins.The stage distribution was distributed in the following manner: 130cases in stage I (85.0%), including 116 cases of Ia and 14 cases of Ib; 13in stage II (8.5%); 9 in stage III (5.9%); and 1 in stage IV (0.7%).

Adjuvant therapy was administered in 86 cases, including hormonaltreatment in 55 (35.9%), chemotherapy in 27 (17.6%), and radiotherapyin 33 (21.6%), either alone or in combination. In contrast, 67 (43.8%)women did not receive any adjuvant treatment.

Rates of RFS and OS for the entire series

During the mean follow-up time of 74.2 (range: 1–396) months,49 (32.0%) patients developed recurrence (Table 1). The mean re-lapse interval was 35.2 ± 35.3 months and varied widely, from 3to 145 months. Of the 143 original stage I/II patients, 44 (30.8%) re-lapsed, and 5 of the 10 original stage III/IV (50.0%) patients relapsed.

The recurrence rate was 78.9% (15/19) in the myomectomy subgroupand 25.4% (34/134) in the hysterectomy subgroup. For women withand without BSO, the recurrence rates were 15.6% (17/109) and 72.7%(32/44), respectively (Table 3). The disease recurred locally in 17cases, at distant sites in 4 cases, and both locally and at distant sites in28 cases. The distant metastasis sites included the abdominal cavity orwall (21 cases), lungs (13), kidneys and ureter (3), bone (3), retroperi-toneal LNs (1), liver (1), spleen (1), and chest wall (1). All patients withrecurrence developed LG-ESS as the recurrence, and no one had UES.

Two patients with recurrence accepted palliative treatment due totheir poor physical condition, preventing more radical treatments, andeventually died from the disease. The remaining 42 patients underwentsurgery, and mainly debulking surgery, with or without postoperativeadjuvant treatment, 13 of whom had macroscopically residual tumorsafter secondary surgery. Castration surgery was implemented inwomenwho had initially accepted the ovary-sparing procedure, exceptin 2 patients in whom ovarian function was continually spared due totheir very young ages. Both of these patients are living free from the dis-ease, and their SAR duration has been up to 3 and 117 months, respec-tively. Tumor control was again achieved in 28 (63.6%) recurrent cases.In total, 9 (5.9%) women died of the disease, and 15 (9.8%) patients cur-rently livewith the disease. In total, 129 (84.3%)women are livingwith-out evidence of tumors (Table 1). For the entire series, the 5-year RFSand OS rates were 66.1% and 95.8%, respectively. The mean SAR timewas 77.5 (range: 1–351) months, and the 5-year SAR rate was 82.9%.

Table 4The rates of relapse free survival (RFS) and overall survival (OS) in the entire series andsubgroups (%).

Parameter RFS Parameter OS

5-Year 10-Year 5-Year 10-Year

The entire series 66.1 49.6 The entire series 95.8 95.8Primary surgery Menstruation statusMyomectomy 0 0 Premenopause 98.9 98.9Hysterectomy 75.4 56.7 Postmenopause 73.3 73.3

BSO Cervical involvement+ 87.0 74.2 + 79.9 79.9− 27.4 7.60 − 98.2 98.2

Resection margins LVSI+ 69.0 50.1 + 85.6 85.6− 43.7 43.7 − 97.8 97.8

Adjacent treatment Adjacent treatmentHT 77.7 63.6 HT 95.2 95.2CT 74.2 67.5 CT 96.2 96.2RT 92.0 65.7 RT 92.3 92.3Observation 54.8 33.9 Observation 96.3 96.3

657H. Bai et al. / Gynecologic Oncology 132 (2014) 654–660

Risk factors related to relapse and survival

Possible risk factors correlated with relapse and survival were ex-plored, and these factors are shown in Table 3. In univariate analyses,BSO, hysterectomy, radiotherapy, and clear resection margins were sig-nificantly associated with relapse. In multivariate analyses, BSO, clearresection margins, and hysterectomy were identified as independentfactors favoring relapse (P b 0.0001, =0.0041, and =0.0075, respec-tively; Fig. 1A–C). Radiotherapy was then removed from the model.Compared with the rate in the hysterectomy group (75.4%), the 5-yearRFS rate in the myomectomy group was 0, with a mean recurrence in-terval of 20.5 (range: 3–53) months. The 5-year RFS rates of patientswith or without BSO were 87.0% and 27.4%, respectively, whereas pa-tients with clear or involved resection margin had 5-year RFS rates of69.0% and 43.7%, respectively (Table 4). In a subgroup analysis, thewomen who underwent hysterectomy and BSO with clear resectionmargins had a 5-year RFS rate as high as 91.5%.

The significant predictors of survival, according to univariate analy-ses, included menstruation status, resection margins, age at diagnosis,stage, myometrial invasion, LVSI, and cervical involvement. Menopause,cervical involvement, and positive LVSIwere independent predictors forsurvival in multivariate analyses (P b 0.0001, =0.0020, and =0.0163,respectively; Fig. 2A–C). Compared with the rates in the menopause,positive cervical involvement, and positive LVSI groups, the 5-year OSrateswere higher in the pre-menopause, negative cervical involvement,and negative LVSI groups (Table 4). In a subgroup analysis, premeno-pausal women without cervical involvement had a 5-year OS rate of100%.

No RFS or OS benefit was found for lymphadenectomy (P = 0.1187and =0.5138, respectively). Initial myomectomy and ovary-sparing

Fig. 1. Relapse free survival (RFS) andOverall survival (OS). The 5- and 10-year RFS-rate for thepositive resection-margins (C) were independent adverse factors for relapse (P b 0.0001, =0.0

procedures both had no significant impact on OS (P = 0.8845 and =0.0810, respectively).

In the recurrent cases, besides the risk factors evaluated above, dis-tant recurrence and macroscopically residual tumor were associatedwith SAR in univariate analyses (P = 0.0137 and=0.0004, respective-ly; Table 5). None of the patients with local recurrence died of the dis-ease. For patients with or without macroscopically residual tumor, the5-year SAR rates were 65% and 100% respectively.

The 5-year RFS rates of women who underwent radiotherapy, hor-monal treatment, or chemotherapy after initial surgery were 92.0%,

entire groupwere 66.1% and 49.6% respectively. Ovary-sparing (A), myomectomy (B), and075,and =0.0041, respectively; panels A, B, C).

Fig. 2. The 5- and 10-year OS-rates for the entire group both were 98.1%. Post-menopause (A), cervical involvement (B), and positive LVSI (C) were significantly associated with survival(P b 0.0001, =0.0020, and =0.0163, respectively; panels A, B, C).

658 H. Bai et al. / Gynecologic Oncology 132 (2014) 654–660

77.7%, and 74.2%, respectively, whichwere higher than the 54.8% 5-yearRFS rates of those patients in the observation group. The three treat-ment modalities had a similar favorable effect on SAR. The 5-year SARrates of patients who underwent radiotherapy, hormonal treatment,and chemotherapy after salvage surgery were 94.1%, 96.0%, and 94.4%,respectively, compared with the 78.6% SAR rate in the observationgroup (P = 0.1774, =0.2450 and =0.1545, respectively; Table 5).

Discussion

Although LG-ESS is relatively indolent, late recurrence and distantmetastases may occur [3,6–10]. The recurrent risk may be as high as

Table 5Risk factors related survival after relapse (SAR).

Parameter DOD OS (%) P valuea

+ − 5-Year 10-Year

Distant recurrence+ 9 23 83.1 83.1 0.0137− 0 17 100 100

Macroresidual tumorsb

+ 7 8 65 65 0.0004− 2 32 100 100

Adjuvant treatmentb

HT 5 22 96.0 96.0 0.2450c

CT 3 18 94.4 94.4 0.1545c

RT 4 17 94.1 94.1 0.1774c

Observation 2 10 78.6 78.6

a Log rank test.b After salvage surgery.c Comparing to observation group.

50% [6,7]. In our study, the 10-yearOS ratewas 95.8%,which is relativelysatisfactory, whereas the 10-year RFS rate was as low as 49.6%. Themean relapse interval was approximately 4.1 years; however, relapsemay occur as late as 12.1 years after the primary treatment. Given thedisease course, a management strategy that controls the primarytumor while prolonging progression-free survival or preventing recur-rence is necessary but has not yet been identified. The present studycompiled 153 LG-ESS cases. This large sample size enabledus to performa robust analysis to identify the important factors affecting the diseaseprognosis and, consequently, to evaluate the effects of different treat-ment strategies on the management of this rare tumor.

The mainstay surgery for LG-ESS

Surgery, generally hysterectomy and BSO, had a definitive effect onpatient prognosis and should be treated as the mainstay initial treat-ment for LG-ESS. In our series, ovary-sparing procedures, positive resec-tion margins, and myomectomy were independent adverse factors forrelapse. For the women who underwent hysterectomy and BSO withnegative resection margins, the 5-year RFS rate was as high as 91.5%.Total hysterectomywith BSO and complete resection of themacroscop-ic lesion should thus be treated as general guidelines for tumor controland prognosis improvement in LG-ESS.

Complete resection of themacroscopic lesion and castration surgerycould also apply to the treatment of relapsed cases, because of the prog-nostic significance ofmacroscopically residual tumor in salvage surgery.For patients with and without macroscopically residual tumor, the 5-year SAR rates were 65% and 100%, respectively (P = 0.0004). Early de-tection and complete excision of recurrent lesions were crucial for im-proving survival.

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Ovary-sparing procedures for LG-ESS

Castration helped to reduce the recurrence risk, consistent with sev-eral studies [10–12], in addition to our own data mentioned above. Incontrast, Shah et al. [13] compiled 384 LG-ESS cases and demonstratedthat ovarian preservation seems to have no effect on the excellent OSof these patients and that adnexal metastasis in LG-ESS is very rare inthe absence of a gross adnexal or extra-uterine tumor. Chan et al. [14]also revealed that younger women (b50 years) with stage I–II ESS (in-cluding UES) who underwent ovary-sparing procedures had similarsurvival rates as patients who underwent BSO. Our data similarlyshowed that initial ovary-sparing procedures had no impact on OS(P = 0.0810), despite being the most important risk factor for relapse.Post-menopausal status, cervical involvement, and positive LVSI wereindependent predictors of survival. For premenopausal womenwithoutcervical involvement, the 5-year OS rate was 100%. The explanation forthis “paradox” may lie in the rarity of the tumor. Due to its rarity, moststudies have been limited to a very small sample size, resulting in the in-clusion of fewer recurrent cases and fatal cases. Thus, these studiescould not perform multivariate analyses to identify independent riskfactors for relapse and survival. Neither Shah nor Chan, although bothincluding a relatively large sample size, provided any details about re-lapse or the subsequent treatment of patients. In our series, the vastma-jority of patients with recurrence ultimately underwent castrationsurgery. Therefore, the negative impact of the ovary-sparing procedureson survival might have been blocked. Thus, ovary-sparing proceduresdo not compromise survival but increase the risk of relapse, which iscorresponding to Yoon's [5] findings. For inert LG-ESS, ovary-sparingsurgeries might be considered in younger women without cervical in-volvement on the premise that they have access to long-term follow-up care. When tumors recur, castration and debulking surgery shouldbe implemented in a timely fashion.

Myomectomy for LG-ESS

LG-ESSwaspredominantly diagnosed inwomen at a fertile age, witha mean age of 41.8 in the present study, and 14.4% patients were non-nulliparous. Fertility-sparing procedures were significantly importantfor these women, yet little relevant information was available in the lit-erature due to the malignancy and high risk recurrence of this tumor.According to our data, myomectomy was not associated with survival(P = 0.8845), and 5 women underwent a successful cesarean deliveryafter initial surgery, which was encouraging. Several case reports havealso shown that fertility-sparing surgery for LG-ESS might be feasible[15–21]. However, this approach independently affected recurrence(P = 0.0075). The 5-year RFS in our series was 0 for patients whounderwent initial myomectomy. Consequently, myomectomy shouldonly be considered for young patientswith a strong desire for future fer-tility, with fully informed consent and having no evidence of infertility.Given the mean recurrence interval was only 20.5 months for thetargeted population, hysterectomy is recommended after the comple-tion of pregnancy and delivery, and the duration for their attempt tobe pregnant should not be too long. In addition, owning to the currentlylimited data, the safety and feasibility of this management necessitatedthe further evaluation.

Role of lymphadenectomy

The role of pelvic and para-aortic lymphadenectomies in LG-ESStreatment remains unclear. In our study, no benefit was found forlymphadenectomy regarding either RFS or OS, and nodal metastases(1/46, 2.7%) and recurrence (1/49, 2.0%) were both rare. Lymphadenec-tomy seemed to have little benefit for women with LG-ESS. However,we could not determine the true incidence of nodal involvement, asonly 30.1% of our patients had undergone an evaluation of their nodalstatus. In the literature, the LN metastasis rate in LG-ESS patients is

reported in a wide range (0–37%) [22]. Dos Santos et al. [4] found thatthe rate of occult LN metastasis was as high as 10% (2/20) in patientswithout clinically evident extra-uterine disease or enlarged LNs. More-over, the prognostic significance of LN metastases has been controver-sial [5,13,14]. Until further study provides more convincing clinicalevidence to clarify the therapeutic andprognostic significance of LNme-tastases, lymphadenectomy should still be recommended for LG-ESSpatients, either to provide prognostic information or to guide postoper-ative treatment.

Adjuvant treatment

For LG-ESS, there has been no consensus on the indications and rolesof postoperative adjuvant treatment. Neither chemotherapy nor radio-therapy was shown to be effective against LG-ESS [23]. ESS tends to ex-press progesterone receptors and appears to be responsive to hormonalmanipulation [24–26]. Beck et al. [12] found that patients receiving pro-gestin vs. expectant management had a slightly lower recurrent rate.Our study showed that adjuvant treatment had favorable effects bothon RFS and SAR, although both of the analyses did not reach statisticalsignificance (Radiotherapy after initial surgery was significantly associ-ated with relapse in univariate analyses, possibly because all of thewomenwho accepted radiotherapy had undergone initial BSO; this fac-tor was removed from multivariate analyses as a confounding factor.).This absence of significancemight be ascribed thatwomenwith adversefactors for relapse and survival had a greater likelihood of being treatedwith adjuvant therapies. These results might thus suggest that adjuvanttreatment still should be conserved for patients with advanced and re-current diseases.

This analysis had several limitations including its retrospective na-ture and single-center design. Additionally, the study spanned over a30-year period, during which progress has been made in ESS diagnosisand treatment.

Conclusions

The present study demonstrated that for LG-ESS patients, hysterecto-mywith BSO and complete resection of themacroscopic lesion should betreated as mainstay initial and salvage treatments. Ovary-sparing proce-dures do not compromise survival but increase the risk of relapse; thuslong-term follow-up should be mandatory for young patients undergo-ing this procedure. Myomectomy should only be considered for youngpatients with a strong desire for future fertility, with fully informed con-sent; whereas hysterectomy is recommended after the completion ofpregnancyanddelivery. However, the therapeutic roles of lymphadenec-tomy and adjuvant treatment deserve further investigation.

Conflict of interest statement

The authors have no conflict of interest to declare.

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