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Mesenchymal Tumors, Pathology of the Uterine Corpus 239
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 7 Myxoid leiomyoma. (a) Cytologically bland
spindle cells are embedded in abundant myxoid matrix. (b) The tumor border is well circumscribed
Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 8 Leiomyoma with variant features. (a)
Lipoleiomyoma consists of scattered adipocytes
IFITM1 (Agoff et al. 2001; Busca et al. 2018; Chu
et al. 2001; Oliva et al. 1995; Parra-Herran et al.
2014). p16 and p53 overexpression is rare among
typical leiomyomas but can be seen in
leiomyomas with bizarre nuclei (Atkins et al.
2008; Chen and Yang 2008; Delgado et al. 2021;
Liang et al. 2015; Mills et al. 2013;O’Neill et al.
2007; Rubisz et al. 2019; Ubago et al. 2016). Loss
of fumarate hydrat ase (FH) staining and 2SC
overexpression is often observed in leiomyomas
with bizarre nuclei (Bennett et al. 2017b; Chan
et al. 2019; Chen et al. 2014; Gregova et al. 2020;
Harrison et al. 2016; Reyes et al. 2014; Siegler
et al. 2018; Zhang et al. 2018).
Molecular Features
Leiomyomas frequently harbor MED12 mutations
(Croce and Chibon 2015; Hayden et al. 2018;Je
surrounded by neoplastic smooth muscle. (b)
A plasmacytic infiltrate is seen in an otherwise typical
leiomyoma
et al. 2012; Kampjarvi et al. 2016; LieglAtzwanger et al. 2016; Makinen et al. 2011;
Makinen et al. 2017; McGuire et al. 2012; Perot
et al. 2012). A large subset of tumors harbor
HMGA2 and HMGA1 rearrangements (Griffin
et al. 2019; Makinen et al. 2017; Mehine et al.
2016). COL4A5 and COL4A6 deletions are infre-
quent (Garcia-Torres et al. 2000; Mehine et al.
2016
). HMGA2 rearrangements, KAT6B-
KANSL1 fusion, and TPCN2-YAP1 fusion have
been detected in cellular leiomyomas (Ainsworth
et al. 2019; Hodgson et al. 2020).
Differential Diagnosis
Endometrial stromal tumor. Highly cellular
leiomyomas can be confused with an endometrial
stromal nodule or low-grade endometrial stromal
sarcoma. Highly cellular leiomyomas, however,
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often show a fascicular growth pattern, elongated
nuclei, thick-walled blood vessels, cleft spaces,
and positivity for desmin, SMA, and
h-caldesmon. CD10 negativity favors a smooth
muscle tumor, but a large subset of highly cellular
leiomyomas may express CD10.
Leiomyosarcoma. Mitotically active and apoplectic leiomyomas may be distinguished from
leiomyosarcoma based on the absence of nuclear
atypia and tumor necrosis. Leiomyomas with
bizarre nuclei lack tumor necrosis and mitotic
activity but often requires extensive sampling to
ensure absence of worrisome feature throughout
the tumor. While p16 overexpression and aberrant
p53 staining are frequently found in
leiomyosarcoma, these staining patterns are also
seen in a subset of leiomyomas with bizarre nuclei.
A diagnosis of myxoid leiomyoma often requires
extensive sampling of the tumor to myometrial
interface to exclude myometrial invasion.
Intravenous Leiomyomatosis
Synonyms
Intravascular leiomyomatosis.
Definition
Intravenous leiomyomatosis is a proliferation of
histologically bland smooth muscle growing
within venous channels, outside the confines of a
leiomyoma.
Clinical Features
• Incidence
Intravenous leiomyomatosis is rare.
• Age
Intravenous leiomyomatosis often affects
women of reproductive age (median, 44 y;
range, 32–82 y) and has rarely been described
in postmenopausal patients (Buza et al. 2014;
Liu et al. 2020; Low et al. 2017; Ordulu et al.
2020; Su et al. 2020).
• Site
Intravenous leiomyomatosis involves
myometrial and occasionally parametrial veins.
Extrauterine extension is seen in 22–50% of
cases and can involve the broad ligament and,
less often, the ovarian and vaginal veins (Buza
et al. 2014; Ordulu et al. 2020;Suetal.2020).
• Treatment
Hysterectomy is often indicated at the time of
surgical intervention. Medical management
with gonadotropin-releasing hormone agonists
or aromatase inhibitors may improve symptoms (Biri et al. 2008; Bodner-Adler et al.
2009). Given an increased risk of abdominal
and thoracic recurrence in intravenous
leiomyomatosis, posttreatment surveillance
imaging is recommended.
• Outcome
Extrauterine extension occurs in approximately 30% of patients and may involve pelvic
veins, vena cava, and heart (Worley Jr. et al.
2009). Rare cardiac involvement may result in
sudden death (Roman and Mirchandani 1987;
Shi and Shkrum 2018). Recurrence may occur
7 months to 15 years after hysterectomy
(Evans 3rd et al. 1981; Grella et al. 1994).
Macroscopy
Multiple white rubbery firm nodules are present
within the myometrium and associated with
worm-like plugs of tumor within myometrial and
occasionally parametrial veins.
Microscopy
Intravenous leiomyomatosis is characterized by
intravascular growth of neoplastic smooth muscle
that resembles usual leiomyoma or leiomyoma variants (Fig. 9a, b) (Carr et al. 2015; Clement et al.
1988;Orduluetal.2020). Cleft spaces,
hyalinization, numerous thick-walled vessels, and
hydropic change are often present (Fig. 9c,
(Clement et al. 1988; Mulvany et al. 1994). Endometrioid glands and stroma within the intravascular
tumor may also be seen (Hirschowitz et al. 2013).
Extravascular leiomyomas are often present and
less circumscribed that the typical leiomyoma.
Immunophenotype
Tumors may express increased p16 and cyclin D1
compared to adjacent myometrium (Ordulu et al.
2020). Tumors frequently express Rb,
SMARCB1, and FH, and are negative for
SOX10 and CAIX (Ordulu et al. 2020).
d)
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 9 Intravenous leiomyomatosis. (a, b) Intravas-
cular, worm-like plugs of tumor are composed of
Molecular Features
Regional losses of 22q, 1p, 1q, 2p, 2q, 13q,
and 14q, and gains of 6p, 2q, 10q, 8q, 8p,
and 1q have been reported (Buza et al. 2014;
Ordulu et al. 2020). der (14) t (12;14) has
been reported in rare tumors (Dal Cin et al.
2003;Quadeetal.2002). MED12 mutations
characteristic of leiomyomas have not been
reported in intravenous leiomyomatosis (Buza
et al. 2014).
Differential Diagnosis
Low-grade endometrial stromal sarcoma. Intravenous leiomyomatosis and low-grade endometrial stromal sarcoma both demonstrate dense
cellularity and vascular involvement. However,
low-grade endometrial stromal sarcoma often
involves the endomyometrium, has a prominent
extravascular component that demonstrates
tongue-like, permeative myometrial invasion,
and lacks large, thick-walled blood vessels and
cleft spaces.
histologically bland neoplastic smooth muscle associated
with numerous prominent thick-walled blood vessels.
(c, d) Polypoid tumor is ensheathed by endothelial cells
Leiomyosarcoma. While vascul ar invasion
can be present, conventional or variant
leiomyosarcomas often demonstrate marked
nuclear pleomorphism, tumor necrosis, and brisk
mitotic activity, features which are absent in intravenous leiomyomatosis. By definition, intravenous leiomyomatosis is composed of smooth
muscle cells that are reminiscent of leiomyoma
or leiomyoma variants.
Smooth Muscle Tumor of Uncertain
Malignant Potential
Synonyms
Smooth muscle tumor of low malignant potential.
Definition
Smooth muscle tumor of uncertain malignant
potential (STUMP) is a smooth muscle neoplasm
that demonstrates some but not all histologic features required for malignancy.
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Clinical Features
• Incidence
STUMPs are rare.
• Age
The median age is 48 (range, 25–85) years
(Croce et al. 2018; Gupta et al. 2018;Ip
et al. 2009).
• Site
STUMPs may be submucosal, intramural, or
subserosal.
• Treatment
Treatment guidelines are limited. For patients
diagnosed with STUMP on myomectomy,
management options include hysterectomy or
surveillance.
Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 10 Smooth muscle tumor of uncertain malig-
nant potential (STUMP). Tumor necrosis seen in an
otherwise typical leiomyoma
• Outcome
STUMPs have a recurrent potential of up to
28% across studies, underscoring the histo-
4. Tumors with diffuse atypia and uncertain
mitotic index.
logic and biologic heterogeneity of these
tumors. The association between histologic
features and clinical behavior is not clear
given aggregation of outcome data from
small case series (Amant et al. 2005; Atkins
et al. 2008;Belletal.1994;Berrettaetal.
2008;Dall’Asta et al. 2014;Guptaetal.
2018;Haetal.2018;Ipetal.2009;
Immunophenotype
STUMPs are variably positive for p16, p53,
Ki-67, p21, BCL2, ER, and PR (Chen and Yang
2008; Ip et al.
2017; Mills et al. 2013). Some
tumors may demonstrate loss of ATRX or
DAXX (Ahvenainen et al. 2018; Makinen et al.
2016; Slatter et al. 2015).
Kalogiannidis et al. 2016;Sungetal.2009;
Ver a s e t a l. 2011).
Molecular Features
Tumors are genetically heterogeneous, ranging from
Macroscopy
Gross features of STUMPs are similar to
leiomyomas.
rare chromosomal alterations to high chromosomal
instability similar to the genomic profile of
leiomyosarcoma (Croce et al. 2015). A subset of
tumors harbor MED12 mutations (Croce and
Microscopy
STUMPs are morphologically heterogeneous, and
Chibon 2015; Perot et al. 2012;Schwetye
et al. 2014).
diagnostic criteria are not well defined.
A diagnosis of STUMP may be considered when
there is uncertainty in criteria for malignancy. The
following tumors may be considered STUMP
(Chow et al. 2017; Gupta et al. 2018; Ip et al.
Differential Diagnosis
Leiomyosarcoma. Morphologic features that fulfill
diagnostic criteria for leiomyosarcoma are diagnosed as such and should not be considered STUMP.
2007;Ipetal.2009; Lim et al. 2013; Pang et al.
2015; Veras et al. 2009):
Leiomyosarcoma
1. Tumors with multifocal or diffuse atypia, 5–9
MF/10 HPF, and no tumor necrosis.
2. Tumors with tumor necrosis only (Fig. 10).
3. Tumors with 15 MF/10 HPF and no tumor
necrosis or atypia.
Definition
Leiomyosarcoma is a malignant smooth muscle
tumor that can show spindle, myxoid, and/or epithelioid morphology.
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Clinical Features
• Incidence
Uterine leiomyosarcoma is rare with an annual
incidence of 0.64 per 100,000 women (Harlow
et al. 1986).
• Age
Median patient age is 51 (range, 23–81) years.
• Site
Uterine leiomyosarcomas are usually intramural but can be submucosal or subserosal.
• Treatment
For patients with a preoperative diagnosis of
leiomyosarcoma and uterus confined disease,
total hysterectomy is recommended with bilateral salpingo-oophorectomy also performed if
peri- and postmenopausal (Park et al. 2008;
Seagle et al. 2017). For patients found to have
leiomyosarcoma postoperatively, completion
hysterectomy is performed if supracervical hysterectomy or myomectomy was previously
done; if the tumor was morcellated, surgical
exploration with complete resection of disease
is recommended. Observation is recommended
for patients with uterus-confined disease, while
chemotherapy is recommended for patients with
advanced disease. Surveillance examination
and imaging is recommended in all patients
regardless of stage due to the high risk of
relapse. Surgical resection or local ablation
may be performed in the setting of localized
recurrence. Chemotherapy is recommended in
patients with metastatic disease. Patients with
hormone receptor-positive leiomyosarcoma,
low disease burden, and indolent course may
benefit from hormone blockade (George et al.
2014;O’Cearbhaill et al. 2010).
• Outcome
Prognosis is poor regardless of stage (Kapp
et al. 2008; Zivanovic et al. 2012). Myxoid
leiomyosarcoma appears to be more aggressive than conventional leiomyosarcoma, but
clinical data for myxoid and epithelioid
leiomyosarcoma is limited (Abeler et al. 2009;
King et al. 1982; Parra-Herran et al. 2016).
Macroscopy
Uterine spindle or epithelioid leiomyosarcoma is
characterized by a single, soft, fleshy, yellow or
tan mass often associated with hemorrhage and
necrosis. Myxoid leiomyosarcoma is often large
and gelatinous.
Microscopy
Conventional or spindle cell leiomyosarcoma is a
densely cellular tumor characterized by fascicles
of spindle cells with markedly pleomorphic nuclei
that are sometimes multinucleated or multilobated, prominent nucleoli, and abundant eosinophilic cytoplasm (Fig. 11a, b). Mitotic activity is
often brisk with numerous atypical forms. Osteoclastic giant cells may be present. Some tumors
may demonstrate foci reminiscent of leiomyoma.
Infarct and tumor necrosis (abrupt transition
between viable and necrotic tumor, viable blood
vessels surrounded by a rim of viable perivascular
tumor) are present, with the latter being a defining
feature of leiomyosarcoma (Fig. 11c, d). Any two
of the following features are diagnostic of spindle
leiomyosarcoma: tumor necrosis, diffuse moderate to severe atypia, and 10 MF/10 HPF
(Fig. 11). Myometrial infiltration and
lymphovascular invasion can be present.
Myxoid leiomyosarcomas are often
paucicellular and composed of spindled to epithelioid cells associated with abundant amphophilic
and sometimes eosinophilic matrix (Fig. 12).
Awide range of nuclear atypia and mitotic activity
can be seen, the latter often dependent on tumor
cellularity. At least one of the following features is
diagnostic of myxoid leiomyosarcoma: any
degree of cytologic atypia, tumor necros is, and
mitotic index of >1 MF/10 HPF. Myometrial
infiltration and vascular invasion are often
present.
Epithelioid leiomyosarcoma consists of round
to polygonal cells that occupy at least 50% of the
overall tumor (Fig. 13a). Criteria for malignancy
are poorly defined due to tumor rarity. In some
reports, epithelioid leiomyosarcoma may be diagnosed in the setting of any degree of nuclear
atypia and tumor necrosis or any degree of nuclear
atypia and 5 MF/10 HPF (Chiang 2021;
Kurman and Norris 1976; Prayson et al. 1997;
Toledo and Oliva 2008). According to the most
recent World Health Organization classification,
however, epithelioid leiomyosarcoma may be
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 11 Leiomyosarcoma. (a) Sheets of tumor cells
form vague fascicles. (b) Diffuse moderate to severe atypia
and brisk mitotic activity are commonly seen. Tumor
Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 12 Myxoid leiomyosarcoma. Markedly atypi-
cal spindle and stellate cells are surrounded by
amphophilic myxoid stroma
diagnosed if at least one of the following features
is present: moderate to severe atypia, tumor necrosis, and 4 MF/10 HPF. A subset of epithelioid
leiomyosarcomas that harbor PGR fusions are
characterized by biphasic patterns of epithelioid/
necrosis is characterized by (c) viable perivascular tumor
surrounded by necrotic debris and (d) an abrupt interface
between viable (left) and necrotic (right) tumor
rhabdoid and spindled cells (Fig. 13b) (Chiang
2021; Chiang et al. 2019; Momeni-Boroujeni
and Chiang 2020). The epithelioid/rhabdoid component exhibits sheets of cells with abundant
eosinophilic cytoplasm, centrally or eccentrically
located irregular nuclei, and prominent nucleoli,
associated with variable but often brisk mitotic
activity. Myxoid matrix may be present. The spindled component is characterized by sheets of
small cells with fusiform nuclei, inconspicuous
nucleoli, scant eosinophilic cytoplasm, and low
mitotic activity.
Immunophenotype
Uterine leiomyosarcomas are positive for desmin,
SMA, and h-caldesmon, but staining patterns may
be weak or focal in poorly differentiated tumors.
CD10, EMA, and cytokeratin expression is often
seen, especially among epithelioid tumors. Most
tumors express ER and PR. Strong, diffuse p16
and aberrant p53 expression are common.
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 13 Epithelioid leiomyosarcoma. (a) Tumor
cells demonstrate marked nuclear atypia and abundant
Diffuse, moderate-to-strong nuclear PLAG1
expression is seen in 50% of myxoid
leiomyosarcomas, including all tumors harboring
PLAG1 rearrangement and a small but significant
subset of PLAG1 fusion-negative tumors (AriasStella 3rd et al. 2019; Chiang 2021; MomeniBoroujeni and Chiang 2020).
Molecular Features
TP53, ATRX,andMED12 mutations are frequently
found among spindle leiomyosarcoma (An et
al. 2017;Yangetal.2015). PLAG1 gene re-
arrangements have been reported in approximately
25% of myxoid leiomyosarcomas; fusion partners
include TRPS1 and RAD51B (Arias-Stella 3rd et al.
2019; Chiang 2021;Momeni-Boroujeniand
Chiang 2020). PGR rearrangements were recently
identified in epithelioid leiomyosarcomas that display biphasic epithelioid/rhabdoid and spindled
features, in which NR4A3 is the fusion in a subset
of tumors (Chiang 2021; Chiang et al. 2019;
Momeni-Boroujeni and Chiang 2020).
Differential Diagnosis
Leiomyoma variants. These tumors may demonstrate histologic features such as increased cellularity and/or mitotic activity, infarct necrosis, or
bizarre nuclei. Since the features are often isolated
findings, they do not fulfill diagnostic criteria for
leiomyosarcoma.
Smooth muscle tumor of uncertain malignant
potential (STUMP). These tumors display some,
eosinophilic cytoplasm. (b) Rhabdoid morphology is characteristic of PGR fusion-positive sarcomas
but not all histologic features of leiomyosarcoma.
A diagnosis of STUMP is applied when there is
uncertainty about diagnostic criteria for
leiomyosarcoma or there is a low risk of recurrence.
Low-grade endometrial stromal sarcoma with
smooth muscle differentiation. Typical low-grade
endometrial stromal sarcoma morphology is usually
present. While rare low-grade endometrial stromal
sarcomas may show brisk mitotic activity, the
mitotic index is low in most tumors. The smooth
muscle differentiation is histologically bland in contrast with most spindle leiomyosarcoma that display
overt nuclear pleomorphism.
High-grade endometrial stromal sarcoma.
High-grade endometrial stromal sarcomas with
YWHAE or BCOR genetic abnormalities often
show myxoid or fibromyxoid morphology that
can be confused with myxoid leiomyosarcoma.
However, tumors with YWHAE rearrangement or
BCOR
internal tandem duplication often demonstrate a high-grade round cell component with
uniform moderate nuclear atypi a. BCOR fusionpositive tumors often lack myogenic differentiation or only display SMA and/or h-caldesmon
staining without desmin expression.
Inflammatory myofibroblastic tumor (IMT).
While these tumors are often spindled, they
often lack severe nuclear atypia and demonstrate a conspicuous inflammatory infiltrate
and only limited myoid expression compared
to spindle leiomyosarcoma. Some inflammatory
myofibroblastic tumors exhibit myxoid change,
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which can be confused with myxoid
leiomyosarcoma. ALK fusion-positive inflammatory myofibroblastic tumors will show diffuse ALK positivity.
NTRK fusion-positive uterine sarcoma. These
tumors may sometimes involve the uterine corpus and mimic spindle leiomyosarcoma. However, the cytologic atypia is often only mild to
moderate, and smooth muscle markers are typically negative. NTRK fusion-positive sarcomas
are positive for pan-TRK, and a subset of them
are positive for CD34 and S100. Pan-TRK
expression can be seen in rare leiomyosarcomas,
and evaluation of other markers, such as desmin,
CD34, and S100, as well as fusion testing are
helpful.
Undifferentiated uterine sarcoma.
Undifferentiated uterine sarcoma is a diagnosis
of exclusion and lacks morphologic and immunohistochemical evidence of cell differentiation.
Perivascular epithelioid cell tumor (PEComa).
PEComa shares histologic and immunohistochemical overlap with epithelioid leiomyosarcoma.
Absence of HMB45 and melan-A staining favors
epithelioid leiomyosarcoma. Presence of HMB45
and melan-A is seen in PEComa and a subset of
epithelioid leiomyosarcoma. In such settings, a
diagnosis of malignant epithelioid neoplasm with
myomelanocytic differentiation may be applied,
and molecularly testing for TSC1/TSC2 mutations
and TFE3 or RAD51B fusions is recommended.
Absence of these genetic abnormalities favors epithelioid leiomyosarcoma.
Endometrial Stromal Nodule
Definition
Endometrial stromal nodule is a benign endometrial stromal tumor that is well circumscribed and
lacks myometrial and lymphovascular invasion.
Clinical Features
• Incidence
Endometrial stromal nodule is rare.
• Age
The median patient age is 47 (range, 23–86)
years.
• Site
Endometrial stromal nodules may involve the
endometrium or endomyometrium or be
entirely intramural (Chang et al. 1990; Dionigi
et al. 2002; Tavassoli and Norris 1981).
• Treatment
A simple hysterectomy is curative. Surgical
staging is not required.
• Outcome
Endometrial stromal nodules are benign. No
recurrences have been reported (Chang et al.
1990; Dionigi et al. 2002; Tavassoli and Norris
1981).
Macroscopy
Endometrial stromal nodule is a solitary, well
circumscribed, fleshy, solid, often yellow to tan
and occasionally white tumor involving the
myometrium or endomyometrium (Chang et al.
1990; Dionigi et al. 2002; Oliva et al. 1995;
Tavassoli and Norris 1981). It can be polypoid
and project into the endometrial cavity (Chang
et al. 1990; Dionigi et al. 2002; Oliva et al.
1995; Tavassoli and Norris 1981). Cystic or gelat-
inous change, hemorrhage, necrosis, and calcifications can be seen (Chang et al. 1990; Dionigi
et al. 2002; Oliva et al. 1995; Tavassoli and Norris
1981).
Microscopy
Tumors are well circumscribed or have only focal
irregularities at the periphery (3 finger-like projections each measuring 3 mm from the main
mass) (Fig. 14a). Most tum ors demonstrate conventional morphology resembling proliferativephase endometrial stroma (Fig. 14b). They are
densely cellular and composed of morphologically uniform and small cells with scant cytoplasm, round to oval nuclei, and inconspicuous
nucleoli that whorl around arterioles. Rare large
thick-walled blood vessels may be present at the
periphery. Mitotic activity is often low. Collagen
bands, foamy histiocytes, and cholesterol clefts
may be present. Variant histologic patterns
include smooth muscle differentiation,
fibromyxoid change, sex cord-like differentiation,
endometrioid glands, and rhabdoid, epithelioid, or
deciduoid morphology.
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 14 Endometrial stromal nodule. The tumor is
(a) well circumscribed and (b) consists of bland spindle
Immunophenotype
The immunohistochemical profile of endometrial
stromal nodule is identical to that of low-grade
endometrial stromal sarcoma (see corresponding
subheading).
Molecular Features
JAZF1::SUZ12 fusion is detected in approximately 60% of tumors (Chiang et al. 2011).
MEAF6::PHF1 fusion was recently reported
(Nomura et al. 2020).
Differential Diagnosis
Low-grade endometrial stromal sarcoma.
Absence of myometrial and lymphovascular invasion distinguishes endometrial stromal nodule
from low-grade endometrial stromal sarcoma.
A diagnosis of endometrial stromal nodule can
be made only in hysterectomy specimens where
the entire tumor to myometrium interface can be
histologically examined. The distinction cannot
be made reliably in limited tissue samples, such
as biopsy, curettage, or myomectomy specimens.
The presence of smooth muscle differentiation
may impart a deceptive circumscription to the
conventional component of a low-grade endometrial stromal sarcoma, mimicking an endometrial
stromal nodule. Metaplastic smooth muscle of
endometrial stromal neoplasia, however, appears
disorganized and associated with arterioles compared to larger, oriented bundles of myometrial
smooth muscle. Endometrial stromal tumors with
cells associated with perivascular whorling reminiscent of
proliferative phase endometrial stroma
limited infiltration which demonstrate more
extensive myometrial infiltration than the typical
endometrial stromal nodule should be diagnosed
as low-grade endometrial stromal sarcoma given
the risk of recurrence (Dionigi et al. 2002; Moore
and McCluggage 2020).
Endometrial polyp with cellular stroma.
Endometrial polyps may sometimes demonstrate cellular stroma but usually demonstrate
the presence of glands. Distinction from an
endometrial stromal tumor is usually straightforward in hysterectomy specimens but may be
difficult in limited samples due to tissue fragmentation. In biopsy or curettage specimens,
any fragment of endometrial stroma without
glands and measuring 5 mm should raise concern for an endometrial stromal neoplasm
(Stemme et al. 2014).
Highly cellular leiomyoma. Highly cellular
leiomyoma and endometrial stromal nodule
share significant histologic overlap due to dense
cellularity, nuclear monomorphism, and
circumscribed or slightly irregular tumor borders.
Thick-walled blood vessels, cleft spaces, fascicular growth, and elongated, cigar-shaped nuclei
favor leiomyoma. A panel of immunohistochemical stains, including CD10 and two smooth muscle markers (i.e., desmin and SMA), may be
helpful (i.e., CD10 positivity and desmin/SMA
negativity favor endometrial stromal nodule), but
there is considerable immunophenotypic overlap
between both tumor types.
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Low-Grade Endometrial Stromal
Sarcoma
Definition
Low-grade endometrial stromal sarcoma is a
malignant endometrial stromal tumor demonstrating low-grade spindle cell morphology and
myometrial and/or lymphovascular invasion.
Clinical Features
• Incidence
Low-grade endometrial stromal sarcoma
is rare.
• Age
Mean patient age is 52 (range, 16–83) years
(Chan et al. 2008).
• Site
Tumors involve the endomyometrium.
• Treatment
Surgical staging, including total hysterectomy
and bilateral salpingo-oophorectomy, is
recommended for patients with uterusconfined disease. For patients with evidence
of extrauterine disease, surgical staging and
cytoreduction are performed if the intraabdominal disease is resectable and there is
no extra-abdominal disease. Other patients are
treated with medical therapy. Observation is
recommended for patients with stage I lowgrade endometrial stromal sarcoma. Adjuvant
endocrine therapy is recommended for patients
with stage II to IV low-grade endometrial stromal sarcoma. Endocrine therapy is
recommended for patients who develop recurrent low-grade endometrial stromal sarcoma
and are treatment naïve or received clinical
benefit from prior endocrine therapy. Chemotherapy may be offered for patients with recurrent or metastatic low-grade endometrial
stromal sarcoma who no longer respond to
endocrine therapy.
• Outcome
Low-grade endometrial stromal sarcoma has
an indolent course. In a Surveillance, Epidemiology, and End Results (SEER) analysis of
endometrial stromal sarcomas, the 5-year
disease-free survival was 91.4–95.4% (Chan
et al. 2008). Late recurrences may occur in up
to 60% of patients and are common even with
early-stage disease (Tse et al. 2011). Low-
grade endometrial stromal sarcoma occurs
most frequently in the abdomen/pelvis
followed by lung (Beck et al. 2012; Cheng
et al. 2011). Patients may achieve long-term
survival following surgical resection of recur-
rent disease (Levenback et al. 1992).
Macroscopy
Tumors consist of multiple yellow to tan, fleshy
nodules involving the myometrium and/or
vasculature.
Microscopy
Low-grade endometrial stro mal sarcoma is characterized by densely cellular islands demonstrating tongue-like myometrial infiltratio n and often
prominent lymphovascular invasion (Fig. 15a).
Most tumors exhibit conventional morphology
resembling proliferative-phase endometrial
stroma and are composed of morphologically uniform and small cells with scant cytoplasm, round
to oval nuclei, and inconspicuous nucleoli that
whorl around arterioles (Fig. 15b). Mitotic activity is usually low and can be brisk in rare cases.
Hyaline plaques and foamy histiocytes are common. Variant histologic patterns include smooth
muscle differentiation (Fig. 15c), fibrous or
fibromyxoid change (Fig. 15d), sex cord-like dif-
ferentiation, and endometrioid glands (Chiang
et al. 2011
2005; Huang et al. 2004; Oliva et al. 1998, 1999,
2007; Yilmaz et al. 2002). Less common patterns
include rhabdoid, epithelioid, or deciduoid morphology; bizarre nuclei; and skeletal muscle or
adipocytic differentiation (Baker et al. 2005).
Immunophenotype
Tumors often demonstrate diffuse, strong CD10,
ER, PR, and IFTIM1 staining and may be positive
for keratins and AR (Busca et al. 2018; Chu et al.
2001; McCluggage et al. 2001; Moinfar et al.
2004; Oliva et al. 2002; Parra-Herran et al. 2014;
Rahimi et al. 2019; Reich et al. 2000). Tumors
often demonstrate absent or only focal cyclin D1
and/or BCOR expression (Chiang et al. 2017; Lee
et al. 2012a). Smooth muscle differentiation is
;D’Angelo et al. 2013; Hrzenjak et al.
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