YGYNO-977077; No.

of pages: 4; 4C:
Gynecologic Oncology xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Impact of oophorectomy and hormone suppression in low grade

endometrial stromal sarcoma: A multicenter review
L.E. Stewart a, T.L. Beck a, N.V. Giannakopoulos b, M.H. Rendi b, C. Isacson c, B.A. Goff a,⁎
a
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Washington Medical Center, Seattle, WA, USA
b
Department of Pathology, University of Washington Medical Center, Seattle, WA, USA
c
CellNetix Pathology & Laboratories, Seattle, WA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Objectives. Low grade endometrial stromal sarcoma (LG-ESS) is a rare cancer with an indolent course. We
Received 28 December 2017 aimed to assess the effectiveness of adjuvant hormonal suppression (HT) with or without oophorectomy
Received in revised form 5 March 2018 (BSO) in prolonging progression free survival (PFS) and overall survival (OS) in patients with LG-ESS.
Accepted 7 March 2018
Methods. We performed a multi-institutional retrospective review of patients treated for low grade LG-ESS
Available online xxxx
from 1985 to 2014. Demographics, treatment and recurrence data were abstracted from medical records. Path-
Keywords:
ologic diagnosis was confirmed by a gynecologic pathologist. Long-term patient-reported outcomes were ob-
Endometrial stromal sarcoma tained via mailed survey.
Progression free survival Results. One-hundred-twelve patients underwent surgery for LG-ESS; 59 had postoperative data with a me-
Adjuvant therapy dian follow-up of 55 months (1–325 months). The mean age at diagnosis was 48.5 years (22–82 years). Forty-
Oophorectomy nine (61%) had stage I disease. The most common presenting symptoms were abnormal uterine bleeding
Hormonal suppression (38%) and pelvic mass (17%). Seventy-one (63%) patients had BSO at the time of diagnosis. Of the 59 patients
with postoperative follow-up information, 49 (73%) underwent BSO, 26 (44%) received HT, 20 (33%) were expec-
tantly managed, and 6 (10%) received chemotherapy, radiation or both. Median PFS for the entire group was
53 months and OS was 63 months. PFS for those who underwent BSO compared with those who retained
their ovaries was 38 vs 11 months, p = 0.071. PFS for HT vs no HT was 28 vs 23 months, p = 0.77.
Conclusions. Consistent with prior series, our results support BSO to prolong PFS in LG-ESS but are limited by
sample size. Larger studies with more complete follow-up are needed to determine the effect of adjuvant hor-
monal suppression.
© 2018 Published by Elsevier Inc.

1. Background high grade subtypes based on histopathologic features, namely mitotic

Low-Grade Endometrial stromal sarcoma (LG-ESS) is a rare, indolent
uterine malignancy. It comprises only 0.2% of all uterine malignancies
and roughly 20% of uterine sarcomas [1,2]. It is known to have an indo-
lent clinical course with nearly 80% of patients presenting with stage I
disease [3]. Regardless of stage at diagnosis, half of those diagnosed
will recur, and recurrences are often delayed, occurring a median of
65 months from diagnosis and with recurrences reported N20 years
after initial diagnosis [3–5]. These factors combine to make LG-ESS a dif-
ficult disease to study prospectively and therefore, the majority of treat-
ment recommendations are based on small case series.
The classification of endometrial stromal sarcoma has varied signifi-
cantly in the last decade. Historically, ESS was classified into low and
⁎ Corresponding author at: University of Washington Medical Center, Department of
Obstetrics and Gynecology, Division of Gynecologic Oncology, 1959 NE Pacific Street,
Box 356460, Seattle, WA 98195, USA.
E-mail address: bgoff@uw.edu (B.A. Goff).
index [6]. In 2008, the terms low-grade and high-grade were aban-
doned, such that those tumors with minimal nuclear atypia and fewer
than 10 mitoses per high powered field were simply called endometrial
stromal sarcomas whereas the diverse group of higher grade tumors
was re-classified as undifferentiated uterine sarcomas (UES) [7]. More
recently however, these diseases have been shown to have distinct mu-
tational patterns linked with clinical behavior and prognosis, prompting
a re-adoption of the original nomenclature [8].
Regardless of classification, LG-ESS is defined by a low mitotic index
and is therefore poorly responsive to chemotherapy. Response to radio-
therapy is not clear with some studies suggesting a survival benefit, al-
though they included high-grade subtypes. Radiation has never been
shown to provide a survival benefit in LG-ESS alone [9]. However, LG-
ESS is thought to be hormonally responsive with near-universal expres-
sion of estrogen and progesterone receptors [10]. This has led many to
postulate that estrogen deprivation via bilateral salpingo-oophorec-
tomy (BSO), or suppressive hormone therapy (HT), or both together,
may improve patient outcomes. Controversy has surrounded the

https://doi.org/10.1016/j.ygyno.2018.03.008
0090-8258/© 2018 Published by Elsevier Inc.

Please cite this article as: L.E. Stewart, et al., Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A
multicenter review, Gynecol Oncol (2018), https://doi.org/10.1016/j.ygyno.2018.03.008
2 L.E. Stewart et al. / Gynecologic Oncology xxx (2018) xxx–xxx

widespread adoption of BSO in the upfront management of this disease
which has a mean age at diagnosis of 48–50 years [11]. Data supporting
any one management strategy is sparse largely due to the rarity of the
disease. This has led to significant practice variation with regard to
counseling and management of pre- and peri-menopausal women
with this disease. We aimed to assess the effectiveness of HT with or
without BSO in prolonging PFS and OS in a large group of women with
ESS. We hypothesized that both HT and BSO would improve PFS in
women with LG-ESS.
2. Materials and methods
We conducted a 30-year, multi-institutional, retrospective chart re-
view which was augmented with long-term, patient-reported out-
comes obtained via mailed survey. This study was approved by the
Institutional Review Boards at the University of Washington/Fred
Hutchinson Cancer Research Center and the Swedish Medical Centers.
We included all patients diagnosed with endometrial stromal sarcoma
at the University of Washington and Swedish Medical Centers in Seattle,
WA between January 1985 and December 2014. Cases of endometrial
stromal sarcoma were identified using diagnostic databases maintained
by the departments of pathology. A total of 112 cases of LG-ESS were
identified between the two institutions (97 from the University of
Washington and 15 from Swedish Medical Centers). All pathologic
specimens were reviewed by a gynecologic pathologist to confirm a di-
agnosis of low-grade endometrial stromal sarcoma. Any cases in which
pathologic review resulted in a change in diagnosis (most commonly to
high-grade ESS or UES), were excluded. All inpatient and outpatient re-
cords were reviewed and demographic data, operative technique, pa-
thology reports, postoperative course, treatment and recurrence data
were abstracted. Stage of disease was determined (when possible)
from operative and pathology reports according to the International
Federation of Gynecology and Obstetrics (FIGO) staging system for en-
dometrial cancer. Adjuvant hormonal suppression was defined as any
oral progestin, aromatase inhibitor, or injectable GnRH agonist. Study
data were collected and managed using REDCap electronic data capture
tools hosted at the Institute of Translational Health Science [12].
We developed a short, 14-item survey to gather long-term, patient
reported outcomes. Items queried included vital status, disease recur-
rence, receipt of additional treatments, and long-term health outcomes
such as dementia, secondary cancers, osteoporosis, and heart disease.
The medical record and public records were searched for most current
mailing address for each patient. Patients for whom a mailing address
was available were sent a survey with a description of the study and a
pre-paid return envelope.
Clinical characteristics were compared using Chi2 test. Kaplan-Meier
method was used for reporting PFS and OS. All survival analysis
included data from both the medical record and survey follow-up. The
log rank test was used to compare progression free and overall survival
between groups with or without initial BSO, receipt of HT (yes/no), or
expectant management following surgery.
3. Results
A total of 112 cases of LG-ESS were identified during the study pe-
riod. The mean age at diagnosis was 48.5 years (22–82 years) and the
mean BMI was 29.3 kg/m2. Racial/ethnic information were available
for 58 women, the majority of whom were Caucasian (87.9%). Six pa-
tients identified as Asian (10.34%) and one patient as Native Hawai-
ian/Pacific Islander (1.7%). Sixty-seven patients had available data on
parity, among whom only 9 (11%) were nulliparous. Of the 80 patients
(71%) for whom stage data were available, 49 had stage I disease
(61%), 8 had stage II disease (10%), and 20 had stage III-IV disease
(25%) (Table 1). The most common presenting symptoms were abnor-
mal uterine bleeding (59%) and pelvic mass (29.5%). Only one patient
was asymptomatic at diagnosis.
With respect to operative data, 71 (63.4%) patients underwent BSO
at the time of initial surgery (Table 1). Of those who underwent BSO,
61 (85.9%) were aged 40 years or older and 29 (40.8%) were aged
50 years or older. Twenty-nine patients had undergone preoperative
endometrial sampling of whom 8 (27%) had a benign finding, 1 (3%)
was read as sarcoma NOS, 18 (62%) were ESS and 2 (6%) had missing
or uninterpretable reports. Thirty-six patients (32.1%) underwent
lymph node sampling, of which 5 (13.8%) were found to have patholog-
ically-confirmed nodal involvement. Eight patients (25%) with ad-
vanced stage disease had operative reports which noted gross residual
tumor.
Surveys were sent to 46 women who had a current mailing address
in the medical record or in available public records. Twenty-nine were
returned to sender and a second attempt at finding a valid address
was unsuccessful. Of the 17 women who presumably received the sur-
vey, 16 were completed corresponding to a 94% response rate. No sur-
veys were returned incomplete. Survey data added an additional 1–
19 yrs of follow-up information for those patients who were reached.
Four surveys provided long-term (10-19 yrs) follow-up data for pa-
tients who otherwise had no follow-up data available in the medical
record.
Postoperative follow-up and management data were available for 59
patients, 49 (73%) of whom underwent BSO, 26 (44%) received HT, 20
(33%) were expectantly managed, and 6 (10%) received chemotherapy,
radiation or both. Median follow-up was 55 months (1–325 months).
Documented recurrences occurred in 42.8% of patients with median
PFS of 53 months and OS of 63 months. Recurrences were predomi-
nantly located in the pelvis (60%) and the lung (13%)) (Table 2).

Table 1
Patient characteristics by surgical and adjuvant management.

BSO No BSO HT Expectant management

N (%) N (%) N (%) N (%)

Mean age at diagnosis (range) 50 (27–82) 45 (22–73) 47 (22–74) 46 (24–62)

Mean BMI (range) 30 (18–45) 28 (20–38) 30 (18–45) 29 (20–43)
Race⁎
Caucasian 32 (45) 16 (50) 22 (69) 14 (61)
Asian 6 (8) 0 (0) 3 (9) 3 (13)
Hawaiian/Pacific Islander 1 (1) 0 (0) 0 (0) 1 (4)
Unknown/not reported 32 (45) 16 (50) 7 (22) 5 (22)
Mean parity (range) 2.1 (0–7) 1.7 (0–5) 2.0 (0–7) 2.1 (0–5)
Stage⁎⁎
I 37 (52) 10 (31) 16 (50) 18 (78)
II–IV 22 (31) 8 (25) 14 (44) 2 (9)
Missing 12 (17) 14 (44) 2 (6) 3 (13)

Percentages may not total 100 due to missing data.

⁎ Chi2 p b 0.001 for HT vs expectant management groups.
⁎⁎ Chi2 p b 0.001.

Please cite this article as: L.E. Stewart, et al., Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A
multicenter review, Gynecol Oncol (2018), https://doi.org/10.1016/j.ygyno.2018.03.008
 L.E. Stewart et al. / Gynecologic Oncology xxx (2018) xxx–xxx 3

Table 2
Rate of Recurrence by BSO.
BSO No BSO p-Value
N (%) N (%)
Recurrence 14 (35%) 8 (66%) 0.051
No recurrence 26 (65%) 4 (33%)
Recurrence rates of those who underwent bilateral salpingo-oophorectomy at the time of
LG-ESS diagnosis (BSO), compared with those who retained their ovaries (No BSO).
Fig. 1. Progression free survival by BSO. Progression free survival among those who
underwent bilateral salpingo-oophorectomy at the time of diagnosis (BSO), compared
with those who retained their ovaries (No BSO).
Among those who underwent BSO at the time of their diagnosis 35%
experienced a recurrence compared to 66% recurrence among women
who retained their ovaries (p = 0.051). PFS was 38 vs 11 months for
those who underwent BSO vs those who retained their ovaries (p =
0.55) (Fig. 1). PFS was not different for those who received adjuvant
HT compared to those who did not (28 vs 23 months, p = 0.77).
There were no significant differences in rate of recurrence based on
other adjuvant treatment modalities including chemotherapy, radia-
tion, or multimodal adjuvant therapy (Table 3).
4. Discussion
LG-ESS sarcoma is difficult to study due to its rarity and indolent na-
ture. Because of this, there are no universally agreed upon treatment
recommendations and the current understanding of treatment re-
sponses are based on small case series. There are also no disease-specific
follow-up recommendations and patients with LG-ESS are often
followed postoperatively according to NCCN or SGO guidelines for en-
dometrial cancer surveillance which may not provide prolonged
enough surveillance for a disease known for delayed recurrences [13].
Our series further supports this with a median progression free survival
of 53 months and a median overall survival of 63 months, with most pa-
tients alive at last known follow up. Although recurrences are delayed,
they remain common. In our series, 42.8% of patients experienced a re-
currence, consistent with the literature which cites a 50% recurrence
risk [3–5]. The common but delayed recurrences of LG-ESS continue to
highlight the need for disease-specific surveillance recommendations
involving prolonged or potentially lifelong surveillance of patients fol-
lowing treatment for LG-ESS.
LG-ESS is also known to be a disease of younger women with a large
population based study utilizing the Surveillance, Epidemiology, and
End Results (SEER) database showing a mean age at diagnosis of
50 years [11]. The mean age at diagnosis in our series was similar at
48.2 years. Additionally, LG-ESS is known ubiquitously express estrogen
and progesterone receptors, raising concerns that retention of ovarian
tissue and/or exposure to unopposed estrogens may increase recur-
rence risk. However, in light of the well-documented risks of early sur-
gical menopause there has been hesitation about widespread adoption
of routine BSO for these women [9,14,15]. Several studies have ad-
dressed BSO with respect to recurrence risk with conflicting results
[6,11,16]. Our study supports the practice of BSO by demonstrating a
trend toward prolongation of both PFS (38 vs 11 months) and OS (45
vs 14 months) in those patients who underwent oophorectomy at the
time of diagnosis, though we faced the same lack of power that plagues
most studies of this disease. Additionally, the risk of recurrence in the
BSO group was 35% compared with 66% in the no BSO group (p =
0.051) which approached statistical significance in the small population
of patients.
Adjuvant hormonal suppression with high dose progestins, aroma-
tase inhibitors or GNRH-agonists may have a survival benefit compara-
ble to that seen in studies supporting BSO, but studies are limited by
heterogeneity in treatments and practice variation. Efficacy of hormonal
therapy has been well documented in the recurrent and advanced dis-
ease settings but has yet to be adopted as routine practice in the adju-
vant setting despite multiple series suggesting a benefit [17–21]. Our
series did not show a difference in PFS by receipt of adjuvant hormonal
therapy though we also noted significant variation in dose, type, and du-
ration of treatment which may have impacted our ability to address this
question. We should also note that there was significant overlap be-
tween the BSO and HT groups which could confound our results.
Our study is unique in that we were able to incorporate long term
patient-reported follow-up data which was obtained via a mailed sur-
vey. Although our actual survey response rate was 34%, the vast major-
ity of the surveys that were not completed, never reached the intended
patient as they had been returned to sender by the postal service due to
an invalid address. Of the 17 surveys which were not returned to sender,
16 were completed and returned. Of the patients who received a survey,
94% responded which demonstrates that patients with this rare tumor
are extremely motivated to contribute to scientific research involving
their disease and that incorporating long-term follow-up data obtained
via survey is feasible when studying rare diseases.
Our study also describes the practice patterns of a heterogeneous
group of gynecologic oncologists who practice in both academic and pri-
vate practice environments. Our results demonstrate a large variation in
practice which resulted in heterogeneous exposure to both oophorec-
tomy and adjuvant hormonal therapy. However, in general it has been
our practice to counsel women to consider BSO at the time of diagnosis,
particularly if childbearing has been completed, and we have typically
reserved adjuvant hormonal suppression for the recurrent setting.
Our paper adds to the current body of literature by presenting one of
the largest series of exclusively LG-ESS patients to date and by
supplementing our findings with long term patient-reported outcomes.

Table 3
Rates of recurrence by alternative adjuvant treatment modalities.

No adjuvant Tx Hormonal Chemotherapy Radiation Multimodal

N (%) N (%) N (%) N (%) N (%)

Recurrence 9 (50%) 9 (32%) 1 (100%) 3 (75%) 2 (66%)

No Recurrence 9 (50%) 19 (67%) 0 (0%) 1 (25%) 1 (33%)

Number and percentage of patients who experienced and did not experience a documented recurrence of their LG-ESS based on the type (if any) of adjuvant therapy they received.

Please cite this article as: L.E. Stewart, et al., Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A
multicenter review, Gynecol Oncol (2018), https://doi.org/10.1016/j.ygyno.2018.03.008
4 L.E. Stewart et al. / Gynecologic Oncology xxx (2018) xxx–xxx
However, as with all studies of this disease, our findings are limited by
sample size and difficulty retaining patients for long-term follow-up.
In the future, such rare and indolent diseases would benefit most from
a rare-disease registry which would allow for prospective acquisition
of long-term follow-up data.
Acknowledgements
REDCap at ITHS is supported by the National Center For Advancing
Translational Sciences of the National Institutes of Health under Award
Number UL1 TR000423.
Conflicts of interest
The authors of this work have no conflicts of interest to disclose.
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