doi:10.1111/jog.14436 J. Obstet. Gynaecol. Res.

2020

Endometrial stromal sarcoma: A review of rare

mesenchymal uterine neoplasm

V.A. Capozzi, L. Monfardini, V. Ceni, A. Cianciolo, D. Butera, M. Gaiano and R. Berretta

Department of Gynecology and obstetrics of Parma, University of Parma, Parma, Italy

Abstract
Objective: This review aims to analyze the pathological aspects, diagnosis and treatment of rare mesenchy-
mal uterine tumors.
Methods: On August 2019, a systematic review of the literature was done on Pubmed, MEDLINE, Scopus,
and Google Scholar search engines. The systematic review was carried out in agreement with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyzes statement (PRISMA). The following words and
key phrases have been searched: “endometrial stromal sarcoma”, “low-grade endometrial stromal sarcoma”,
“high-grade endometrial stromal sarcoma”, “uterine sarcoma”, “mesenchymal uterine tumors” and “uterine
stromal sarcoma”. Across these platforms and research studies, five main aspects were analyzed: the biologi-
cal characteristics of the neoplasms, the number of cases, the different therapeutic approaches used, the
follow-up and the oncological outcomes.
Results: Of the 94 studies initially identified, 55 were chosen selecting articles focusing on endometrial stro-
mal sarcoma. Of these fifty-five studies, 46 were retrospective in design, 7 were reviews and 2 randomized
phases III trials.
Conclusion: Endometrial stromal sarcomas are rare mesenchymal uterine neoplasms and surgery represents
the standard treatment. For uterus-limited disease, the remove en bloc with an intact resection of the tumor
(without the use of morcellation) is strongly recommended. For advanced-stage disease, the standard surgi-
cal treatment is adequate cytoreduction with metastatectomy. Pelvic and para-aortic lymphadenectomy is
not recommended in patients with Low-grade Endometrial Stromal Sarcoma (ESS), while is not clear
whether cytoreduction of advanced tumors improves patient survival in High-grade ESS. Administration of
adjuvant radiotherapy or chemotherapy is not routinely used and its role is still debated.
Key words: endometrial cancer, endometrial stromal sarcoma, high-grade, low-grade, mesenchymal uterine
tumor.

Introduction Nolan and Taylor first described the pathological fea-

Endometrial stromal sarcoma (ESS) is part of a rare
and complex group of mesenchymal uterine neo-
plasms and represents 1% of all uterine malignancies.1
ESS is the second most common mesenchymal uterine
tumor after leiomyosarcomas and Figures 15% of
malignant mesenchymal neoplasms of the uterus.2
tures of these cancers and studied their clinical behav-
ior in 1966.3 The neoplasms were divided
morphologically into two groups: one with pushing
margins (stromal nodules) and one with infiltrating
margins (endolymphatic stromal myosis or stromal
sarcoma). Stroma nodule was considered benign
while tumors with infiltrating margins were separated

Received: April 19 2020.

Accepted: July 30 2020.
Correspondence: L. Monfardini, MD, Department of gynecology and obstetrics of Parma, University of Parma, via Gramsci 14, 43125,
Parma, Italy.
Email: luciano.monfardini@gmail.com

© 2020 Japan Society of Obstetrics and Gynecology 1

V. A. Capozzi et al.
by mitotic activity: tumors containing fewer than
10 mitotic figures in 10 High-Power Field (endolym-
phatic stromal myosis—low grade), and those con-
taining 10 or more mitotic figures in 10 HPF (stromal
sarcoma—high grade). Over time, different authors
have expanded and integrated the description and
classification of this type of neoplasm on the basis of
both pathological characteristics and survival.
In 1982, Evans et al.4 defined that there was no evi-
dence of any intermediate form or continuum
between endometrial stromal sarcoma and poorly dif-
ferentiated endometrial sarcoma and that considering
them as being simply low-grade and high-grade vari-
eties of a single neoplasm was not supported by suffi-
cient empirical data.
The WHO 2003 classification5 provided only two
categories of stromal sarcomas being recognized
based on cytologic atypia, namely, low-grade endo-
metrial stromal sarcoma (LG-ESS) and
undifferentiated endometrial sarcomas (UES). It has
shown that the ’UES’ category is too broad, including
a wide range of heterogeneous tumors with different
clinical behavior and outcome, morphology and
genetic features. In 2012, the improvement of cytoge-
netics and molecular biology of these high-grade EES
led to their reinstitution by the current WHO classifi-
cation (2014) as a distinct group of ESS, defined as a
malignant tumor of endometrial stromal derivation
with high grade, round-cell morphology sometimes
associated with a low-grade spindle cell component
and characterized by a t(10;17) leading to the
YWHAE-NUTM2 rearrangement.6 Later in 2018, the
third group of ESS characterized by cells with uni-
form but definite nuclear atypia, permeative myo-
metrial invasion and a clinical behavior intermediate
between LG-ESS and UES were also introduced in the
WHO classification.7
The current WHO classification (2014) acknowl-
edges four categories within the endometrial stromal
family of tumors: endometrial stromal nodule, low-
grade endometrial stromal sarcoma, high-grade endo-
metrial stromal sarcoma and undifferentiated uterine
sarcoma.8 LG-ESS and HG-ESS account for 86% and
14%, respectively, of all endometrial stromal sarcomas
as reported in a large study on uterine mesenchymal
tumors.9
The aim of this review is to analyze the pathogene-
sis, prognosis and various therapeutic strategies of
women suffering from endometrial stromal sarcoma.
Given the rarity of the pathology, few studies and
with few cases are present in the literature. In this
2 © 2020 Japan Society of Obstetrics and Gynecology
contest, the review can play an important role in help-
ing clinicians in the correct management of the
patient.
Materials and Methods
In August 2019, a systematic review of the literature
was done on Pubmed, MEDLINE, Scopus and Google
Scholar search engines. The following words and key
phrases have been searched: “endometrial stromal
sarcoma”, “low-grade endometrial stromal sarcoma”,
“high-grade endometrial stromal sarcoma”, “uterine
sarcoma”, “mesenchymal uterine tumors” and “uter-
ine stromal sarcoma”. Three authors carried out the
research independently (CVA, ML, CV), discarding
the repeated studies. Case reports, non-English arti-
cles and non-gynecological studies have been
removed from the research. All relevant works cited
by the analyzed studies were also included in the
research. The systematic review was carried out in
agreement with the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyzes statement
(PRISMA).10
Of the 94 initially identified, fifty-five were chosen
selecting articles focusing on endometrial stromal sar-
coma to eliminate duplication. Of the fifty-five studies
that met eligibility criteria, forty-six were retrospec-
tive in design, seven were reviews and two random-
ized phases III trials (as reported in Figure 1). Across
these studies, the biological characteristics of the neo-
plasms, the number of cases, the different therapeutic
approaches used, the follow-up and the oncological
outcomes were analyzed (Table 1).
Endometrial Stromal Nodule (ESN)
As the name implies, ESN is a benign tumor that usu-
ally arises in the perimenopausal period, even though
it can afflict women of different ages.11 Abnormal
uterine bleeding is the most frequent symptom, how-
ever, 10% are asymptomatic and diagnosis of ESN is
made incidentally after a hysterectomy performed for
other reasons.12 ESN can develop into the
myometrium (intramural), submucosal or it can grow
into the endometrial cavity (polypoid form). This is a
well-limited non-encapsulated tumor with a soft and
yellow cut surface. Necrosis, hemorrhage areas or cys-
tic degeneration may be present13 and irregular mar-
gins are rarely present.11 Although ESN has got

Studies examinated from
PubMed, MEDLINE, Scopus,
Review
FIGURE 1 Selection of N= 7
the studies
expansible features, myometrial and lymphovascular
invasion must be absent. Microscopically cells present
features of proliferative phase endometrial stroma
with smooth muscle and other differentiation or
infarct-like necrosis.13 Scant cytoplasm, with a little
cytological atypia, and a mitotic index of up to five
mitoses per 10 high power fields are normally pre-
sent.11 Positivity for Neprylisine (CD10), Estrogen
Receptor (ER), Progesterone Receptor (PR) has been
reported; immunohistochemistry is negative for
Wilms’ Tumor protein (WT1), androgen receptor,
Smooth Muscle Actine (SMA), cytokeratin, b-catenin,
vimentin, muscle-specific actin and desmin
negativity.11
Highly cellular leiomyomas (HCL), a benign neo-
plasm characterized by densely cellular tissue that
involves the surrounding myometrium, is often con-
fused with ESN.14 A feature that helps to differentiate
HCL from ESN is vascularization: arterioles with
small-caliber and thin walls are present in ESN, while
large-caliber and thick muscular walls arterioles are
typical of HCL.15 Recurrence of ESN is rare but cases
have been reported in the literature even after many
years of follow-up.11,12 Only after a careful sampling
and examination of the tumor border on hysterec-
tomy specimens a definitive diagnosis can be made.
ESN and LG- ESS share the same immunohistochemi-
cal profile, which makes this aspect uninformative for
a differential diagnoses.13 Clinical and pathological
differences of ESN, LG-ESS, HG-ESS and UUS are
showed in Table 2.
© 2020 Japan Society of Obstetrics and Gynecology
Review on endometrial stromal sarcoma.
Google Scolar
N= 94
Excluded
N= 35
(18 case report; 7 non
gynecological studies, 5 duplicate
studies, 5 non-English studies
Total studies included
N= 55
Retrospective studies Randomize phase III
trials
N= 46
N= 2
Low-Grade Endometrial Stromal
Sarcoma (LG-ESS)
Overview
After leiomyosarcomas, LG-ESS represents the most
common stromal tumor by frequency. It usually
affects perimenopausal women, but occasionally
arises in young women and adolescents.16 Risk factors
for this neoplasm were extensively studied; they
include obesity and diabetes, younger age at menar-
che, tamoxifen intake or estrogen use and pelvic radi-
ation.17,18 Abnormal uterine bleeding, pelvic pain and
dysmenorrhea are the most frequent symptoms pres-
ented by patients. About one-third of patients present
symptoms such as extrauterine spread, while one-
fourth are asymptomatic.19 This neoplasm principally
arises from uterine corpus; rarely it occurs first in
organs such as ovary, abdominal cavity, vulva and
vagina.13 Extrauterine pelvic extension of LG-ESS is
also frequently associated with endometriosis and the
most common extrauterine site is the ovary.20
Pathology
The growth of these tumors can be submucosal or
intramural. The borders are defined and it usually
presents a pattern of permeation into the
myometrium and parametrial tissue called ’worm-
like’.13 Macroscopically there might be areas of hem-
orrhage with necrosis and cystic degeneration while
soft nodules can be recognized between the endome-
trium and the myometrium. LG-ESS rarely appears as
3
4
TABLE 1 Features of some studies analyzed
Author Years Patients Type of Histotype/ Surgery Metastatic lymph Adjuvant Disease-specific Main findings
number study stage nodes (no. of treatment survival (5 years)
patients (no. of patients—
with LN metastatic/ type
no. of of treatment)
lymphadenectomy
V. A. Capozzi et al.

procedures)

Chang et al. 1990 117 Retrospective case- ESN n: 8 114/117 - 15 Non-hormonal Stage I: 98% The
series LG-ESS n: chemotherapy; Stage III: 35% outcome differences between Stages
92 14 Hormonal Stage IV: 50% I, III, and IV are statistically
HG-ESS n: therapy; significant;
14 32 RT; Neither MI nor cytologic atypia was
53 None predictive of tumor recurrence for
treatment patients with Stage I tumors
Chan et al. 2008 831 Retrospective case- G1: 108 775/831 28/282 205 RT; Stage I: 91.7% Older patients, black race, advanced
series G2: 300 611; Stage II: 52.8% stage, higher grade, lack of primary
G3: 288 15 Unknown. Stage III: 61.5% surgery, and nodal metastasis were
Unknown: Stage IV: 41% independent prognostic factors for
135 poorer survival.
Zhang et al. 2019 40 Retrospective case- HG-ESS 40/40 3/15 33 CHT; Stage I: 78% The stage of the disease, size of the
series 13 RT; Stage II-IV: 18% tumor, minimum and average values
5 Hormonal of CA125, menopause, history of
therapy uterine leiomyoma, and
endometriosis were independent risk
factors for OS.
The combination of surgery with
radiotherapy and chemotherapy
may improve the PFS of patients in
the early stage of the disease.
Amant et al. 2007 34 Retrospective case- Stage I: 22 31/31 1/6 7 Hormonal Not analyzed Need for surgical castration (BSO) in
series Stage III: 4 therapy premenopausal women with the
Stage IV: 5 early-stage disease should be
discussed with the patient on an
individual basis;
Data support the current practice to
administer adjuvant hormonal
treatment.
Evans et al. 1982 18 Retrospective case- LG-ESS 11/18; 18/18 unknown 6 RT; LG-ESS 33,3% The first study that analyzed the
series HG-ESS 3 CHT HG-ESS 5,5% clinicopathological differences
7/18 between ESS and Poorly
differentiated endometrial sarcoma;
The extent of the tumor was the major
prognostic factor in both groups;
mitotic rate had no prognostic
significance in either category;

© 2020 Japan Society of Obstetrics and Gynecology

 TABLE 1 Continued
Author Years Patients Type of Histotype/ Surgery Metastatic lymph Adjuvant Disease-specific Main findings
number study stage nodes (no. of treatment survival (5 years)
patients (no. of patients—
with LN metastatic/ type
no. of of treatment)
lymphadenectomy
procedures)

Malouf et al. 2012 30 Retrospective case- LG-ESS 0/30 29/30 13/29 9 Brachytherapy Stage I-II: 31.4%; Neither staging system (FIGO vs AJCC)
series HG-ESS +/− RT Stage III-IV: 18.7% was optimal for risk stratification.
30/30 18 CHT Multimodal therapy was recommended
after surgery.
Ran Cui et al. 2017 20 Retrospective case- LG-ESS 20/20 20/20 0/14 10 CHT; 100% (Disease-free Surgical resection is the foremost
series 4 RT; survival 90%) treatment for LG-ESS patients with
1 Hormonal recurrence or distant metastasis.
therapy; Hormonal treatment may be beneficial
8 None for unresectable or residual tumors.
treatment.
Jay P. Shah 2008 848 Retrospective case- LG-ESS 848/848 LG-ESS 7/100 196 RT LG-ESS 92% The performance of lymph node

© 2020 Japan Society of Obstetrics and Gynecology

et al. series 384/848 HG-ESS 26/143 HG-ESS 25% dissection alone, regardless of the
HG-ESS USS 4/44 finding of any microscopic positive
320/848 nodes, did not have an effect on
USS overall survival in LG-ESS.
144/848 Neither lymph node metastasis nor
ovarian preservation seems to affect
the overall survival of LH-ESS patients.
G. Garg et al. 2010 464 Retrospective case- LG-ESS 464/464 - 109 RT LG-ESS The 5-year overall survival among LG-
series 310/464 Stage IA 100% ESS was significantly better in stage
HG-ESS Stage IB 93.5% IA patients compared to patients
96/464 HG-ESS with stage IB;
USS 58/464 Stage IA 51.4% Tumor size was not found to be an
Stage IB 43.5% independent predictor of survival
after controlling for stage in both
LG-ESS and HG-ESS.
Seagle et al. 2017 3797 Retrospective case- LG-ESS 2414 LG-ESS LG-ESS 87/759 LG-ESS: LG-ESS The best treatment of HG-ESS is early
series HG-ESS 2311/2414 HG-ESS 141/571 115/2218 CHT < 5 cm 95.6% and complete surgical resection
1383 HG-ESS 385/1975 RT 5–10 cm 90% including lymphadenectomy.
1366/1383 307/2035 >10 cm 76.1% Women without lymphadenectomy
Hormonal HG-ESS had survival similar to women with
therapy < 5 cm 50.8% positive lymph nodes;
HG-ESS: 5–10 cm 37.1% Modest survival benefits of adjuvant
444/886 CHT >10 cm 23.4% chemotherapy and radiotherapy for
483/886 RT HG-ESS was provided in this study.
69/1288
Hormonal
therapy
Review on endometrial stromal sarcoma.

5
(Continues)
6
TABLE 1 Continued
Author Years Patients Type of Histotype/ Surgery Metastatic lymph Adjuvant Disease-specific Main findings
number study stage nodes (no. of treatment survival (5 years)
patients (no. of patients—
with LN metastatic/ type
no. of of treatment)
lymphadenectomy
V. A. Capozzi et al.

procedures)

Yan-Yan 2019 40 Retrospective case- HG-ESS 34/40 3/20 33 CHT Stage I 75% Patients with advanced HG-ESS (stage II–
Zhang series 13 RT Stage II-IV 15% IV) were associated with poor prognosis.
et al. 5 Hormonal The stage of disease, size of the tumor,
therapy minimum and average values of
CA125, menopause, history of
uterine leiomyoma, and
endometriosis were independent risk
factors for OS;
The combination of surgery with RT and
CHT may improve the PFS of patients
in the early stage of the disease.
P. A. Argenta 2007 105 Retrospective case- LG-ESS 72 LG-ESS 72/72 LG-ESS 2/23 LG-ESS: LG-ESS 90% Low-grade and high-grade endometrial
et al. series HG-ESS 31 HG-ESS HG-ESS 2/13 3 CHT HG-ESS 40% stromal sarcomas represent two
UUS 2 31/31 USS 0/2 6 RT distinct clinical entities.
UUS 2/2 30 Hormonal HGESS patients with extrauterine
therapy disease, the presence of residual
1 CHT + RT disease greater than 2 cm had a
3 Hormonal+RT significant effect on median survival
1 CHT+ Median survival was 52 months for
Hormonal those who underwent optimal
28 none cytoreduction vs 2 months for those
HG-ESS with suboptimal residual disease
8 RT The impact of cytoreduction was not
2 CHT + RT seen in LGESS patients with
1 Hormonal+RT extrauterine disease.
1 Hormonal
+CHT
19 none
USS
1 CHT
1 none
Reshu 2017 38 Retrospective case- LG-ESS 28/38 38 - 8 RT LG-ESS 74.4% Incomplete surgery and no adjuvant
Agarwal series HG-ESS 3 Hormonal HG-ESS 31.3% treatment in ESS are associated with
et al. 10/38 therapy poor DFS;
1 CHT+ RT Complete staging surgery is associated
1 Hormonal with improved DFS;
+CHT Resection of recurrent disease is
1 Hormonal+RT associated with survival advantage.

© 2020 Japan Society of Obstetrics and Gynecology

 TABLE 1 Continued
Author Years Patients Type of Histotype/ Surgery Metastatic lymph Adjuvant Disease-specific Main findings
number study stage nodes (no. of treatment survival (5 years)
patients (no. of patients—
with LN metastatic/ type
no. of of treatment)
lymphadenectomy
procedures)

Gunsu 2019 37 Retrospective case- LG-ESS 37 3/21 3 RT 72% Hormone therapy after surgery should
Kimyon series 7 CHT be considered a viable option for
Comerta 12 Hormonal decreasing the LGESS recurrence
et al. therapy rate, regardless of the disease stage.
1 Hormonal
+CHT
Weimin Xie 2017 17 Retrospective case- LG-ESS 17 - 15 Hormonal 100% Fertility-sparing surgery may be
et al. series 6 Stage IA therapy considered for young patients with
11 Stage IB stage IA low-grade ESS who wish to
preserve their fertility.
Patients should be carefully selected

© 2020 Japan Society of Obstetrics and Gynecology

and fully informed of the risk of
recurrence; they have the right to
make their own decisions regarding
therapy.

Abbreviations: BSO, bilateral salpingo-oophorectomy; CHT, chemotherapy; DFS, disease free survival; ESN, endometrial stroma nodules; HG-ESS, high grade endometrial stro-
mal sarcoma; LG-ESS, low grade endometrial stromal sarcoma; MI, myometrial invasion; OS, overall survival; RT, radiotherapy; USS, undifferentiated stromal sarcoma.
Review on endometrial stromal sarcoma.

7
V. A. Capozzi et al.
a pure cystic mass. The microscopic myometrial and
lymphovascular invasion is characterized by ’tongue-
like’ patterns; this feature is a key point for the dis-
tinction between LG-ESS and ESN. Microscopically,
LG-ESS resembles the proliferative phase of endome-
trial stroma featuring small cells with oval to spindle
nuclei ordered in sheet surrounded by spiral arteriole-
like vessels. The mitotic index is usually low: about
5/10 per high power fields, but in some cases can be
higher.
Positivity for CD10, WT-1, vimentin, actins, Inter-
feron Induced Transmembrane Protein 1 (IFITM1),
estrogen, androgen, and progesterone receptors is
typically seen at the immunohistochemistry.21 CD10
is not a specific marker for LG-ESS and it is present in
some smooth muscle tumors like leiomyosarcoma
and highly cellular leiomyomas. Immunohistochemis-
try may be useful to distinguish ESS from smooth
muscle tumors, although there is no single specific
marker for ESS. The use of immunostains panel that
includes CD10 and smooth muscle markers like
desmin, h-caldesmon or smooth muscle heavy chain
myosin is important for the distinction between ESS
and other tumors that have an overlapping
immunophenotype.22 In a recent study, H. Hwang
et al.23 found that the combination of ER(+)/PR
(+)/CD10(+)/GEM(−)/h-caldesmon(−)/transgelin(−)
can predict ESS vs Leiomysarcoma of the Uterus
(ULMS). The use of novel antibodies (GEM, trans-
gelin) in association with the well-established immu-
nohistochemistry panel seem to be useful in
distinguishing ESS from ULMS predicting different
clinical course and helping in the management.23
Recurrent chromosomal translocations were found
with the increasing utilization of cytogenetics since
the early 1990s. The most common translocation
reported is t(7;17)(p16;q21), followed by t(6;7) or other
forms of 6p21-rearrangements, t(10;17)(q22;p13) and
t(X;17)(p21-p11;q23).24
The translocation t(7;17) (p15;q21) determines the
fusion between two zinc-finger proteins (JAZF1 and
SUZ12); this genetic fusion was discovered in 2001.25
Further studies have shown that JAZF1-SUZ12 fusion
is the most frequent gene aberration in ESS and seems
to be the cytogenetic hallmark of ESN and LG-ESS.26
This gene fusion is present in about 75% of ESN, 45%
of LG-ESS and in about 14 HG-ESS. Several authors
suggest that JAZF1-SUZ12 fusion should become a
specific tool when the diagnosis of ESS is unclear or
difficult and it might be useful to differentiate LG-ESS
from other smooth muscle uterine tumors.26,27 Micci
8 © 2020 Japan Society of Obstetrics and Gynecology
et al.28 have demonstrated the recombination between
the PHF1 gene (PHD finger protein 1, from chromo-
somal band 6p21) and JAZF1 (JAZF1-PHF1). Further
studies have shown the recombination between PHF1
and other genes (EPC1, MEAF6 or BRD8); these genes
fusions encode proteins involved in transcriptional
regulation29 and their presumed oncogenic effects
may be a lead part of the pathogenesis of ESS.30
Dewaele et al.31 have discovered a novel gene fusion
(MBTD1-CXorf67) in LG-ESS with t(X;17)(p11.2;
q21.33), although the detection of the encoded protein
and the pathological mechanism explanation requires
further studies. Less common fusions include
JAZF1-BCORL1, and BRD8-PHF1 and ZC3H7B-
BCOR.30 A novel fusion that combines MEAF6
(located on 1p34) and SUZ12 (located on 17q12) was
reported for the first time by Makise et al.,32 however,
the prevalence of this fusion is estimated to be
low (< 5%).
Imaging
Accurate preoperative diagnosis of LG-ESS is not yet
available with imaging modalities. The most common
ultrasound features are multiseptated cystic areas and
multiple small areas of cystic degeneration.33 Loca-
tion, margin, the conformation of the lesion could
modify the ultrasound findings. In a recent study con-
ducted by Ludovisi et al. ESS showed the highest per-
centage of visible normal endometrium (91.7%) and
regular tumor borders (60.4%) and were less vascu-
larized than the other sarcomas (score 1–2 in 20 of
47 tumors with reliable color Doppler information,
42.5%).34 Magnetic resonance allows the characteriza-
tion of early stage and provides a differential diagno-
sis with endometrial carcinoma. LG-ESS may appear
as a polypoid endometrial mass, with low signal on
T1-weighted images and heterogeneously increased
high T2 signal.35 The myometrial invasion of these
tumors is typically shown as cutting delimited. A
more diffuse and destructive manner is more com-
mon with UES.35 Myometrial involvement by lym-
phatic and vascular invasion is characterized by
’worms-like’ extension bands within the normal
myometrium of low signal intensity on T2-weighted
images remind a “bag of worms”.35 Compared to
endometrial carcinoma, ESS usually shows larger size,
more contrast enhancement, irregular margin, nodu-
lar extension into the myometrium and marginal
nodularity due to tumor extension along vessels and
lymphatics.36 ESS can be similar to an intramural
 TABLE 2 Clinical and pathological differences of endometrial stroma nodule (ESN), low grade ESS (LG-ESS), high grade (HG-ESS) and undifferentiated
uterine sarcoma (UUS)
ESN
Age Perimenopausal
Symptoms AUB 10% asymptomatic
Growth Intramural (into the
myometrium),
submucosal, polypoid
form (into the endometrial
cavity)
Macroscopy Well-limited non-
encapsulated tumor soft
and yellow cut surface
© 2020 Japan Society of Obstetrics and Gynecology
Histology Cells present features of
proliferative phase
endometrial stroma; scant
cytoplasm, little
cytological atypia
lymphovascular invasion Must be absent
Mitotic activity Up to 5 mitoses per 10 HPF
Immunohistochemistry Positive: CD10, ER, PR
Negative: WT1, androgen
receptor, SMA,
cytokeratin, b-catenin,
vimentin, muscle-specific
actin, and desmin
Abbreviations: AUB, abnormal uterine bleeding; HPF, high power field.
9
LG-ESS HG-ESS USS
Perimenopausal occasionally Menopause Postmenopausal
young women and
adolescents
AUB, pelvic pain, AUB, symptoms related AUB, with/without
dysmenorrhea to extra-uterine spread manifestations of
extrauterine disease
Submucosal or intramural Polypoid features usually Destructive infiltration
with extensive into the uterine wall
infiltrative growth
The borders are defined; Hemorrhage and Necrosis and
’wormlike’ pattern of necrosis areas; hemorrhage are
permeation into the myometrial invasion is extensive presents
myometrium/parametrial usually present
tissue
Areas of hemorrhage with Round and large cells Highly atypical cells
necrosis and cystic growing in rough nests arranged in sheets/
degeneration; features of or in glandular pattern fascicles, without the
proliferative phase of features of
endometrial stroma; small proliferative-phase
cells with oval to spindle endometrial stroma;
nuclei ordered in sheet severe nuclear
surrounded by spiral pleomorphism, high
arteriole-like vessels mitotic activity; lack
smooth muscle/
endometrial stromal
differentiation
’Tongue-like’ patterns Present Present
5/10 per 10 HPF, in some >10 per 10 HPF >10 per 10 HPF
cases can be higher
Positivity: CD10, WT-1, Positivity: cyclin D1; No specific
vimentin, actins, IFITM1, Negative: CD10, ER, immunophenotype
ER, androgen, and PR and PR is present, reflecting
the heterogeneity of
these tumors
Review on endometrial stromal sarcoma.
V. A. Capozzi et al.
leiomyoma with cystic degeneration appearing as a
myometrial mass.
Treatment
LG-ESS has got a favorable prognosis, however, late
recurrence can occur even in patients with early-stage
disease; this requires a long-term follow-up. Surgery
is the most important procedure in the management
of patients with LG-ESS. The primary surgical treat-
ment is hysterectomy and bilateral salpingo-
oophorectomy (BSO). Cytoreduction is recommended
in advanced tumors with extrauterine
manifestations,37 however, in a study conducted by
Leah et al.,38 was showed the cytoreductive surgery is
less important in LG-ESS with no impact on survival.
In these cases, the surgery has to be tailored to the
patient, depending on symptoms, features of the
pathology and with or without palliative intent. LG-
ESS is hormone-dependent and BSO could play an
important role in ceasing hormone production. Preser-
vation of the ovaries, performed in perimenopausal
women, causes an increased rate of recurrence as was
found in several studies.39,40 LG-ESS has high levels
of steroid receptors and metastasizes most frequently
from the uterus to the ovaries. Chu et al.41 suggest
that the lack of ERβ expression in endometrial stromal
sarcoma may be a marker of malignancy and ERT
may be harmful in patients with low-grade endome-
trial stromal sarcoma; other studies,17 however,
argued that the preservation of the ovary has no sig-
nificant effect on OS. Hormone replacement therapy
for the menopausal syndrome is contraindicated and
this supported the benefits of BSO for women with
LG-ESS. According to Ran Cui et al.42 ovary-sparing
procedures might be considered in young patients
with early-stage disease. Due to the rate of late recur-
rence and distant metastases long-term follow-up is
mandatory.43 According to Weimin Xie et al. Young
patients with stage IA LG-ESS who want a pregnancy
may benefit from fertility-sparing surgery. High risk
of recurrence is present when a fertility-sparing sur-
gery is made for stage IB LG-ESS; however, rescue
therapy seems to be effective for local recurrence and
does not affect survival outcomes.44 A careful selec-
tion of patients and accurate information about the
risk of recurrence should be done. Several studies
have investigated the utility of lymphadenectomy in
LG-ESS patients. The recent literature reports that the
lymph node metastasis rate is between the 7%45 and
9.9%,46 more frequent locally within the pelvis.36 A
significant improvement in survival was not
10
associated with lymphadenectomy. Shah et al.45 found
that there were no statistically significant differences
in the 5-year survival rate between node positive LG-
ESS and node-negative LG-ESS (86% vs. 95%).
ESS tend to recur trans-peritoneally or in the lungs
suggesting that this disease is not characterized by
lymphatic metastasis; this could explain the small
effect on survival of the nodal metastasis.47 Surgical
removal of bulky lymph nodes is considered part of a
cytoreductive procedure.48 Pelvic and para-aortic
lymphadenectomy is not recommended in patients
with LG-ESS. Morcellation allows us to remove volu-
minous myomas in minimally invasive surgery; how-
ever, its use should be avoided when malignancy is
suspected. Techniques for safe specimen extraction,
using insufflated isolation bags or transvaginal speci-
men retrieval via endoscopic bags, are now in pro-
gress and may represent a new use of morcellation in
a laparoscopic approach.49
There is no consensus regarding the role of adju-
vant treatment. Chemotherapy has not proved effec-
tive for the treatment of LG-ESS as several studies
have shown.43 The expression of ER and PR by LG-
ESS leads to the use of hormonal treatment; this
appears to be effective in reducing the recurrence.
Postoperative treatment with progestins such as
megestrol and medroxyprogesterone acetate or AI are
routinely administered for residual or recurrent dis-
eases.50 The use of mifepristone as single agent has
demonstrated a 25% stable disease response rate.
Higher results may be obtained with the combined
use of megestrol acetate plus tamoxifen, although
other studies need to prove this therapy scheme. A
recent study showed that the use of megestrol acetate
as adjuvant therapy is associated with a decrease in
the recurrence.51 Hormonal treatment should be con-
sidered after surgery routinely and could be used in
recurrent disease; however, further investigations are
needed to establish the right dose and duration of the
treatment.41
LGESS is a slow-growing tumor with an indolent
clinical course characterized by relapses that can
occur also a long time after surgical treatment. Abdo-
men and lungs are the most frequent sites of recur-
rence.17 The recurrence rate is about 10%, although, in
several studies, the rate was higher.42,43,52 Surgery
may have a role also in recurrent disease and radical
cytoreduction seems to be associated with prolonged
survival.49 The role of hyperthermic intraperitoneal
chemotherapy (HIPEC) in association with cyto-
reductive surgery has been investigated but further
© 2020 Japan Society of Obstetrics and Gynecology

studies are needed to improve the use of this
approach. A flow chart showing treatment strategy is
present in Figure 2.
High-Grade Endometrial Stromal
Sarcoma (HG-ESS)
Overview
The HG-ESS was re-introduced with the 2014 WHO
classification. The identification of YWHAE-
NUTM2A/B gene fusion (also known as YWHAE-
FAM22A/B) provided objective support to the
existence of a subcategory of ESS that is intermediate
between LG-ESS and UUS.13 HG-ESS is clinically
aggressive and frequently presents extrauterine dis-
ease as the first presentation; for such manifestations
it’s primary to differentiate this neoplasm from LG-
ESS providing an accurate treatment.15
Abnormal uterine bleeding and extra-uterine
spread symptoms are usually present at the diagnosis.
Advanced-stage disease (stages II-IV) at the diagnosis
and recurrences after surgical treatment complicate
patient management. According to Pautier et al.,53 the
median progression-free survival (PFS) and OS
ranged from 7 to 11 months and from 11 to
23 months, respectively. In a report conducted by
Garg et al.,54 the 5-year overall survival was worse in
HG-ESS than LG-ESS. There is a significant difference
in 5-years OS between women with stage IA LG-ESS
and stage IB, but not among women with HG-ESS.
Cervical involvement is a significant prognostic factor
in HG-ESS while age, race and stage play a predictor
role only in LG-ESS. In a recent study conducted by
Zhang et al.,55 CA125 value and endometriosis were
independent risk factors for PFS; stage of the disease,
size of the tumor, minimum and average values of
CA125, menopause, history of uterine leiomyoma and
endometriosis were identified as independent risk fac-
tors for OS.
Pathology
Macroscopically, HG-ESS can present polypoid fea-
tures usually with extensive infiltrative growth. Hem-
orrhage and necrosis areas are frequently present.13
Microscopically, infiltrative pattern into the
myometrium and angiolymphatic invasion are pre-
sent. The cells are usually round, larger than those of
LG-ESS, growing in rough nests or reminding a glan-
dular pattern. Mitotic activity is often greater than
10 per 10 high-power fields and necrosis is usually
© 2020 Japan Society of Obstetrics and Gynecology
Review on endometrial stromal sarcoma.
present. HG-ESS is typical negative to CD10, ER and
PR at the immunochemistry, but shows strong diffuse
cyclin D1 immunoreactivity (>70% nuclei).21 Impor-
tant myometrial invasion is usually present in HG-
ESS; this is not typically seen in LG-ESS. Molecular
testing may be useful for differential diagnosis:
HGESS is characterized by t(10;17), whereas most LG-
ESS have abnormalities involving 7p15 and 6p21.21 A
novel type of HG-ESS was discovered by Lien
N. Hoang et al.56: ESS that harbor ZC3H7B/BCOR
gene fusions share significant morphologic overlap
with myxoid leiomyosarcoma. Targeted sequencing
and fluorescence in situ hybridization can help the
pathologist in differentiating the molecular subtypes
of ESS, although further studies are necessary to
improve this diagnostic tool.
The key points to consider for the right evaluation
of HG-ESS are emphasized in a study by Nucci21; a
mitotic activity >20–30 mitoses/10 high-power fields
and loss of hormone receptors are important features
for the diagnosis. Smooth muscle markers are not pre-
sent in HG-ESS (while epithelioid leiomysarcomas is
typically positive). Positivity for c-kit may be diffuse
although this marker is not helpful in the differential
diagnosis of an epithelioid tumor involving the peri-
toneum. DOG1 (Discovered on GIST-1) is more spe-
cific in the distinction between HG-ESS and
Gastrointestinal Stromal Tumor (GIST). Another fea-
ture of this tumor is a diffuse positive for cyclin D1
while is negative for Epithelial Membrane Antigen
(EMA) and cytokeratins.
Chromosomal translocation—t(10;17)(q22;p13) was
found to result in YWHAE-NUTM2A or YWHAE-
NUTM2B genetic fusions. Tumors that harbor this
aberration are associated with high-grade morphol-
ogy, high stage disease at presentation, aggressive
clinical behavior and disease recurrence.57 YWHAE-
NUTM2 genetic rearrangements and JAZF1/SUZ12/
EPC1/PHF1 genetic rearrangements are mutually
exclusive58; this feature could improve the diagnosis
and differentiation between LG-ESS and more aggres-
sive forms, although its clinical and therapeutic utility
needs to be proven. In a recent study,59 Fletcher JA
et al. investigated the presence of internal tandem
duplication (ITD) involving the 30 end of the
transcriptional repressor gene BCOR in a series of
HG-ESS and USS with uniform nuclear features and
diffuse cyclin D1 expression. This genetic alteration
appeared to be less common and mutually exclusive
with YWHAE-NUTM2 rearrangement. High-grade
uterine sarcomas with BCOR ITD usually affect
11
V. A. Capozzi et al.
ESS
Early Stage
Fertility Sparing Ovary-Sparing Hysterectomy +
Treatmenta Surgeryb BSO
Hormonal
Treatmentc
Long-Term
Follow Up
FIGURE 2 Treatment strategy for ESS
young patients with a prognosis that is intermediate
between low-grade ESS and undifferentiated uterine
sarcoma. According to this study, USS presenting the
pathologic features mentioned before should be tested
for BCOR ITD; if BCOR ITD is present, the neoplasm
should be classified as a BCOR ITD-positive high-
grade uterine sarcoma.”
Treatment
The lead treatment consists of hysterectomy and BSO
(without morcellation). Adnexa preservation in
premenopausal women with HG-ESS could be dis-
cussed and its role is not completely clear.60 Metasta-
ses of pelvic and/or para-aortic lymph nodes are
associated with a poorer prognosis. Adjuvant treat-
ment after primary surgery does not seem to improve
the prognosis of this neoplasm61 and is not clear
whether cytoreduction of advanced tumors improves
patient survival. A multicenter retrospective analysis
shows that cytoreduction of high-grade ESS has a
positive effect on survival,38 in contrast to LG-ESS.
This study suggests the importance of an aggressive
12
Multidisciplinary
approach
Advanced Stage
or Recurrent
Disease
Possible Not Resecable
Resection Disease
Cytoreductive Palliative
Surgery Treatment
Targeted
Treatment
and almost complete primary cytoreduction; the sur-
vival in patients with high-grade tumors depends on
the residual disease after surgery with a negative
prognostic impact and, as for other sarcomas, surgical
removal of metastasis should be considered.62
Adjuvant therapy
Post-operative therapy could improve survival in
patients with HG-ESS, but its role is still debated and
there are contrast dates in the literature.
The Gynecological Cancer Group of the EORTC
(European Organization for Research and Treatment
of Cancer) demonstrated that adjuvant external pelvic
radiation did not improve PFS and OS among women
with FIGO I and II stage HG-ESS. In another study61
postoperative pelvic radiotherapy with or without
brachytherapy correlated with improved PFS (19.1 vs
6.5 months; P = 0.04) and OS (54.5 vs 16.7 months;
P = 0.01) in a univariate analysis seems to decrease
locoregional recurrence. Survival benefits of this pro-
cedure, however, are not confirmed. An increase in
the 3-year disease-free survival rate was shown by the
© 2020 Japan Society of Obstetrics and Gynecology

SARCGYN study63 where adjuvant poly-
chemotherapy followed by pelvic radiotherapy
(RT) was compared with RT alone, although further
investigations are necessary due to the limited data
available. Doxorubicin, cisplatin, ifosfamide and pacli-
taxel are the cytotoxic agents active in advance or
metastatic disease.64 Persistent and/or recurrent HG-
ESS have a poor response to chemotherapy treatment;
the effectiveness of this therapy is only 5–27% if recur-
rence occurs after the first-line chemotherapy.65
Undifferentiated Uterine Sarcoma
Overview
This rare and aggressive tumor with no specific line
of differentiation shows alternative morphological
and immunohistochemical features compared to
endometrial sarcomas.13 USS seems to follow genetic
pathways, which are distinct from those of LG-ESS
and HG-ESS.66 Specific translocations or aberration
was not found between low-grade ESS to UES. Chro-
mosomal aberrations in endometrial sarcomas are het-
erogeneous and do not clearly correlate with the
histologic grades. The only exception is the chromo-
somal deletion on 7p in LG-ESS, present in 55.6% of
these tumors; which seems to play a role in tumor
development and progression.67 Patients affected by
USS are typically postmenopausal (mean age is
60 years) with abnormal uterine bleeding with/with-
out manifestations of the high-stage extrauterine dis-
ease.19 High-stage disease (Stage III/IV) is present in
more than 60% of patients at the diagnosis with a
very poor prognosis (<2-year survival).19
Pathology
Necrosis and hemorrhage are extensively present in
the tissue, but the most important macroscopical fea-
ture is a destructive infiltration into the uterine wall.68
Highly atypical cells are arranged in sheets or fasci-
cles without the features of proliferative-phase endo-
metrial stroma.13 Myometrial invasion, severe nuclear
pleomorphism, high mitotic activity and/or tumor
cell necrosis and lack of smooth muscle or endome-
trial stromal differentiation are other important fea-
tures for diagnosis while the lymphovascular
invasion is common. No specific immunophenotype
is present, reflecting the heterogeneity of these
tumors. CD10 is variably positive and is not usually
helpful68; estrogen and progesterone receptors are
weakly positive or negative. UUS is a diagnosis of
© 2020 Japan Society of Obstetrics and Gynecology
Review on endometrial stromal sarcoma.
exclusion; a right diagnosis should be made after
exclusion of other more common high-grade neo-
plasms (leiomyosarcoma, carcinosarcoma, rhabdo-
myosarcoma, sarcomatous overgrowth in a Mullerian
adenosarcoma, undifferentiated endometrial carci-
noma and diffuse large B-cell lymphoma).13 UUS har-
bor a complex karyotype and cytogenetic analysis,
and show many structural and numerical chromo-
somal aberrations such as missense TP53 mutations.69
Imaging
At the ultrasound, USS appears like a solid tissue
with inhomogeneous echogenicity, irregular borders
containing cystic areas with jagged walls with a mod-
erate to rich vascularization at the color doppler. A
multicenter study showed that undifferentiated endo-
metrial sarcomas manifested the highest percentage of
absent shadowing (27/31, 87.1%), irregular tumor
borders (23/31, 74.2%) and hemorrhagic or ground
glass echogenicity of cyst fluid (6/15, 40%).34 At the
MRI, UUS typically appears as a polypoid mass in an
expanded endometrial cavity, showing heterogeneous
signal intensity on both T1- and T2-weighted images.
Compared with normal myometrium USS shows a
heterogeneous contrast enhancement with iso- or
hyperintense features, allowing differentiation from
endometrial carcinoma.35
Treatment
The standard treatment provides hysterectomy and
BSO. The role of lymphadenectomy remains contro-
versial, similar to the surgical treatment of ESS.70 Che-
motherapy might be considered given the risk for the
hematogenous spread and distant metastases; how-
ever, conclusive data on its use is not yet available.60
The persistent and recurrent disease has similar
behavior of soft tissue sarcomas with a poor
prognosis.
Conclusion
Endometrial stromal sarcomas are rare mesenchymal
uterine neoplasms. Data from prospective, large ran-
domized studies are still lacking due to the rarity of
these tumors. Surgery represents the standard treat-
ment for this disease. For uterus-limited disease
(early stage), the removal en bloc with an intact re-
section of the tumor (without the use of mor-
cellation) is strongly recommended, even if the
diagnosis of ESS was accidental. According to
13
V. A. Capozzi et al.
several large studies,71,72 occult uterine sarcoma is
present on the order of 1 in 1700 to 7 in 100 000 in
women undergoing hysterectomy for presumed
benign fibroids; morcellation should be performed
only when malignancy is excluded. For advanced-stage
disease, the standard surgical treatment is adequate
cytoreduction with metastatectomy. Pelvic and para-
aortic lymphadenectomy is not recommended in
patients with LG-ESS while it is not clear whether cyto-
reduction of advanced tumors improves patient survival
in HG-ESS; survival in these patients correlates to the
residual disease at the completion of initial surgery and
many studies provide the need of an aggressive cyto-
reduction. Administration of adjuvant radiotherapy or
chemotherapy is not routinely used and its role is still
debated. The survival benefits of adjuvant treatment are
uncertain, especially for complete cytoreduction cases
and further investigations are needed to understand the
real advantage of this approach. HG-ESS and UUS with
inoperable, locally advanced, recurrent and/or meta-
static diseases have a poor response to chemotherapy
treatment. Molecular biology is becoming a crucial point
to account for an accurate diagnosis and treatment,
although further efforts are needed to improve the
knowledge of these neoplasms and provide better treat-
ment for the patients.
Disclosure
The authors declare that they have no conflict of
interest.
Ethics Statement
This article does not contain any studies with human
participants or animals performed by any of the
authors.
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