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Mesenchymal Tumors, Pathology of the Uterine Corpus 249
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 15 Low-grade endometrial stromal sarcoma.
(a)Infiltration of the myometrium is often tongue-like.
(b) Small spindle cells with scant cytoplasm and oval to
characterized by desmin, SMA, h-caldesmon, and
HDAC8 staining, but foci of conventional morphology may also demonstrate desmin and SMA
positivity (de Leval et al. 2006). Inhib in,
calretinin, melan-A, WT1, and CD99 may highlight sex cord-like elements (Baker et al. 1999;
Baker and Oliva 2007; Irving et al. 2006; Moinfar
et al. 2004; Oliva et al. 2002; Sumathi et al. 2004).
Molecular Features
JAZF1::SUZ12 fusion is the most common,
followed by JAZF1::PHF1, EPC1::PHF1, and
MEAF6::PHF1 fusions (Ali et al. 2014; Chiang
et al. 2011; Hodge et al. 2016; Hrzenjak et al.
2005; Huang et al. 2004; Jakate et al. 2013;
Micci et al. 2003, 2014; Nucci et al. 2007; Oliva
et al. 2007; Panagopoulos et al. 2012 ). MBTD::
EZHIP (CXorf67), BRD8::PHF1, EPC2::PHF1,
EPC1::SUZ12,andJAZF1::BCORL1 have also
been documented (Brunetti et al. 2018; Dewaele
et al. 2014; Dickson et al. 2018; Micci et al. 2017).
round nuclei whorl around delicate arterioles. Variant features are common and include (c) smooth muscle differentiation and (d) fibrous change
Differential Diagnosis
Endometrial stromal nodule. Both low-grade
endometrial stromal sarcoma and endometrial
stromal nodule resemble proliferative-phase
endometrial stroma and cannot be distinguished
in limited tissue samples such as endometrial
curettage or myomectomy specimens since tissue
fragmentation precludes adequate histologic
examination of the tumor to myometrium
interface. In hysterectomy specimens, extensive
sampling of the tumor to myometrium interface is
recommended in the setting of a well
circumscribed endometrial stromal tumor. While
some irregularity of the tumor to myometrium
interface may be seen in endometrial stromal nodule (see corresponding section), any endometrial
stromal tumor demonstrating myometrial and/or
lymphovascular invasion is diagnostic of lowgrade endometrial stromal sarcoma. Some tumors
may demonstrate myometrial infiltration that is
more extensive than the typical endometrial
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stromal nodule but less than the usual low-grade
endometrial stromal sarcoma and have been
described as endo metrial stromal tumors with limited infiltration. Such lesions should be diagnosed
as low-grade endometrial stromal sarcoma given
the risk of recurrence (Dionigi et al. 2002; Moore
and McCluggage 2020).
Highly cellular leiomyoma. Highly cellular
leiomyomas often have fascicular growth of spindle cells, large thick-walled blood vessels, and cleft
spaces. There may be some irregularity at the
periphery, but highly cellular leiomyomas lack
overt myometrial and lymphovascular invasion
characteristic of low-grade endometrial stromal
sarcoma. A panel of immunostains including
CD10 and at least two smooth muscle markers
(desmin, SMA, and h-caldesmon) is often helpful.
CD10 positivity in the absence of myogenic differentiation favors an endometrial stromal tumor,
while myogenic differentiation without CD10
staining favors a smooth muscle tumor. However,
CD10 is not specific, and some smooth muscle
tumors may express this marker. Endometrial stromal tumors with smooth muscle differentiation will
also be positive for smooth muscle markers.
High-grade endometrial stromal sarcoma.
High-grade endometrial stromal sarcomas with
YWHAE rearrangement and BCOR internal tandem duplication (ITD) may show a low-grade
spindle cell component reminiscent of low-grade
endometrial stromal sarcoma; however, they also
demonstrate a high-grade round cell component
characterized by cells with large nuclei and
mitotic index of 10 MF/10 HPF and diffuse,
strong nuclear expression of cyclin D1 and
BCOR. High-grade endometrial stromal sarcoma
with BCOR fusion may resemble low-grade endometrial stromal sarcoma with fibromyxoid or
myxoid change, but frequently has increased
nuclear atypia, mitotic activity, and diffuse, strong
cyclin D1 and BCOR expression.
Adenomyosis with sparse glands.
Adenomyosis may occasionally show foci without glands or involvement of vascular spaces.
However, gland- poor adenomyosis is usually an
incidental finding with no mass noted on gross
examination. Adjacent areas of typical
adenomyosis with glands are usually present.
Adenosarcoma. In contrast to low-grade endometrial stromal sarcoma with glands,
adenosarcomas have phyllodes growth, periglandular stromal condensation, and glands
throughout the tumor.
Intravenous leiomyomatosis. Intravenous
leiomyomatosis and low-grade endometrial stromal sarcoma are both characterized by dense cellularity and intravascular growth. However,
intravenous leiomyomatosis demonstrates fascicular growth of spindle cells, large thick-walled
blood vessels, and cleft spaces.
Leiomyosarcoma. Leiomyosarcomas lack
conventional endometrial stromal sarcoma morphology and frequently display marked nuclear
pleomorphism and brisk mitotic activity compared to low-grad e endometrial stromal sarcoma
with smooth muscle differentiation.
Uterine tumor resembling ovarian sex cord
tumor. Sex cord features are only a focal finding
in endometrial stromal tumors which often also
show other variant features.
High-Grade Endometrial Stromal
Sarcoma
Definition
High-grade endometrial stromal sarcoma is a
malignant endometrial stromal tumor with highgrade round and/or spindle cell morphology that is
sometimes associated with a low-grade spindle
cell component.
Clinical Features
• Incidence
High-grade endometrial stromal sarcoma
is rare.
• Age
Among high-grade endometrial stromal sar-
comas of all genotypes, the median patient
age is 50 (range, 14–74) years (Chiang et al.
2017; Croce et al. 2013;Juckettetal.2019;
Lee et al. 2012b; Marino-Enriquez et al. 2018;
Sciallis et al. 2014; Zou et al. 2020). The
median age of patients w ith BC OR ITD posi-
tive high-grade endometrial stromal sarcoma
is 42 (range, 14–59) years (Chiang et al. 2017;
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Juckett et al. 2019; Marino-Enriquez
et al. 2018).
• Site
High-grade endometrial stromal sarcomas
involve the endomyometrium (Chiang et al.
2017; Croce et al. 2013; Juckett et al. 2019;
Lee et al. 2012b; Marino-Enriquez et al. 2018;
Sciallis et al. 2014; Zou et al. 2020).
• Treatment
Surgical staging, including total hysterectomy
and bilateral salpingo-oophorectomy, is
recommended for patients with uterusconfined disease. For patients with extrauterine
disease, surgical staging and cytoreduction
may be performed if there is no extraabdominal metastatic disease and intraabdominal disease is resectable (Leath 3rd
et al. 2007; Tanner et al. 2012). Clinical benefit
of routine lymphadenectomy remains controversial (Leath 3rd et al. 2007). Patients who are
not surgical candidates, including those with
extra-abdominal metastatic disease, are offered
medical treatment. Anthracycline-based therapy may benefit patients with recurrent
YWHAE::NUTM2A/B fusion-positive highgrade endometrial stromal sarcoma
(Hemming et al. 2017).
• Outcome
High-grade endometrial stromal sarcomas
appear to be more clinically aggressive than
low-grade endometrial stromal sarcomas,
with several small studies suggesting higher
rates of extrauterine disease and lym ph node
metastasis (Lee et al. 2012b; Lewis et al. 2018;
Zou et al. 2020).
Macroscopy
High-grade endometrial stromal sarcomas are
often bulky, intracavitary, and/or intramural, tanyellow, fleshy masses; hemorrhage and necrosis
are often present (Lee et al. 2012b; Lewis
et al. 2018).
Microscopy
High-grade endometrial strom al sarcomas ma y
demonstrate exp ansil e, permeative, or infiltrative growt h, often with more than one pattern
of invasion seen (Croce et al. 2013; Lee et al.
2012b; Lewis et al. 2018). Lymphovascular
invasion, brisk mitotic activity, and necrosis
are often present (Lee et al. 2012b; Lewis et al.
2018). Tumors with YWHAE::NUTM2A/B
fusions demonstrate round cells with scant to
moderate eosinophilic or amphophilic cytoplasm and intermediate-size round to oval nuclei
with irregular nuclear contours, vesicular chromatin, and variably distinct nucleoli (Fig. 16a)
(Aisagbonhi et al. 2018; Croce et al. 2013;Lee
et al. 2012b; Lee and Nucci 2015). A fibrous or
fibromyxoid spindle cell component resembling
variant low-grade endometrial stromal sarcoma
is frequently present (Lee et al. 2012b). Pseudopapillary and pseudoglandular architecture,
pseudorosettes, rhabdoid morphology, and sex
cord-like differentiation are rare (Amant et al.
2011; Lee et al. 2012b). Tumors with ZC3H7B::
BCOR fusions display haphazard fascicles of
spindle cells associated with variable amounts
of myxoid matrix (Fig. 16b) (Chiang et al. 2017;
Hoang et al. 2017; Lewis et al. 2018). The cells
have scant to moderate and eosinophilic or occasionally abundant and blue-gray cytoplasm as
well as intermediate-size oval, spindle, or
round nuclei with even chromatin, and variably
distinct nucleoli (Chiang et al. 2017;Hoang
et al. 2017; Lewis et al. 2018). Collagen plaques
are common; entrapped endometrioid glands
may be present (Chiang et al. 2017;Hoang
et al. 2017; Lewis et al. 2018). Tumors with
BCOR ITD show features of both high-grade
endometrial stromal sarcomas with YWHAE::
NUTM2A/B and ZC3H7B::BCOR fusions and
consist of high-grade round, high- and lowgrade spindle cells, and myxoid matrix
(Fig. 16c). Some tumors harboring low-grade
endometrial s tromal sarcoma-associated gene
fusions (i.e., JAZF1 or PHF1 gene
rearrangement) may exhibit foci of high-grade
histology at the time of or years after initial
diagnosis (Zou et al. 2020). High-grade foci
demonstrate nuclear enlargement, prominent
nucleoli, and brisk mitotic activity often associated with sclerotic and/or myxoid stroma.
A low-grade endometrial stromal sarcoma component is usually present and demonstrates conventional or variant histology (Zou et al. 2020).
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 16 High-grade endometrial stromal sarcoma.
(a) YWHAE fusion-positive tumors demonstrate a highgrade round cell component (top left) often associated
with a low-grade spindle cell component (bottom right).
Immunophenotype
The high-grade round cell component of tumors
harboring YWHAE::NUTM2A/B fusion is characterized by strong and diffuse nuclear staining for
cyclin D1 and BCOR; it may also be positive for
pan-Trk, c-KIT, CD56, and CD99, and is negative
for ER, PR, and DOG1 (Chiang et al. 2017; Lee
et al. 2012a). The low-grade spindle cell component of these tumors shows similar CD10, ER, PR,
cyclinD1, and BCOR expression profiles as lowgrade endometrial stromal sarcomas. Tumors harboring ZC3H7B::BCOR fusion often demonstrate
strong and diffuse nuclear cyclin D1 staining;
however, diffuse nuclear BCOR expression with
variable intensity in seen in only 50% of lesions.
They are frequently positive for CD10 and show
variable ER, PR, and pan-Trk positivity. Focal
SMA and/or h-caldesmon may be seen in a subset
of tumors, but desmin is usually negative. Tumors
with BCOR ITD show at least focal CD10, panTrk, and strong and diffuse BCOR and cyclin D1
expression throughout high- and low-grade components. Focal desmin staining is rare, while SMA
and h-caldesmon are negative. ER and PR status is
unclear with only one case reported to have both
markers absent. High-grade endometrial stromal
(b) BCOR fusion-positive tumors consist of atypical spindle cells surrounded by abundant myxoid matrix. (c)
Tumors with BCOR internal tandem duplication often
demonstrate high-grade round cells and myxoid stroma
sarcomas harboring low-grade endometrial stromal sarcoma-associated fusions are often positive
for CD10, ER, and PR; negative for BCOR and
cyclin D1; and display heterogeneous p53
staining consistent with a wild-type p53 expression pattern (Mohammad et al. 2021). However,
rare cases may demonstrate decreased ER or PR
expression and/or strong and diffuse cyclin D1
and BCOR staining.
Molecular Features
High-grade endometrial stromal sarcomas may
harbor YWHAE::NUTM2A/B fusions (Cotzia
et al. 2019; Croce et al. 2013; Hemming et al.
2017; Lee et al. 2012c; Lee et al. 2012b; Micci
et al. 2016; Sciallis et al. 2014; Stewart et al.
2014), ZC3H7B::BCOR fusions (Chiang et al.
2017; Hoang et al. 2017; Lewis et al. 2018), and
BCOR ITD (Chiang et al. 2017; Cotzia et al. 2019;
Juckett et al. 2019; Marino-Enriquez et al. 2018).
BCOR rearra ngement with other fusion partners,
including L3MBTL2, EP300, NUTM2G
RALGPS1, MAP7D2, RGAG1, ING3, NUGGC,
KMT2D, and CREBBP, are less common
(Dickson et al. 2018; Lin et al. 2020). Rare
EPC1::SUZ12, JAZF1::BCORL1 and BRD8::
,
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PHF1 fusions have also been reported (Allen et al.
2017; Cotzia et al. 2019; Dickson et al. 2018).
High-grade histology may be seen in rare tumors
harboring low-grade endometrial stromal
sarcoma-associated gene fusions (i.e., JAZF1::
SUZ12 and JAZF1::PHF1). CDK4 and MDM2
amplification is common among tumors with
BCOR rearrangement (Kommoss et al. 2020; Lin
et al. 2020). NTRK3 mRNA upregulation and
ESR1 mRNA downregulation are often seen in
tumors with YWHAE fusion and BCOR genetic
abnormalities (Momeni-Boroujeni et al. 2021).
Differential Diagnosis
Low-grade endometrial stromal sarcoma.Compared to low-grade endometrial stromal sarcoma,
high-grade endometrial stromal sarcoma shows
increased nuclear atypia, prominent nucleoli, and
higher mitotic activity, often with a mitotic index of
10 MF/10 HPF. Round cell morphology characteristic of tumors with YWHAE fusion or BCOR
ITD and fibromyxoid morphology characteristic of
tumors with BCOR fusion may mimic low-grade
endometrial stromal sarcoma with variant morphology (i.e., epithelioid, deciduoid, fibrous, and
fibromyxoid change and sex cord-like differentiation in low-grade endometrial stromal sarcoma).
However, low-grade endometrial stromal sarcomas
with variant features often demonstrate conventional and/or other types of variant morphology
that are otherwise absent in high-grade endometrial
stromal sarcoma. Diffuse and strong cyclin D1
expression and/or diffuse BCOR staining of any
intensity in the round cell component of YWHAE::
NUTM2 fusion positive tumors or throughout
tumors with BCOR fusion or ITD is helpful when
those markers are negative or only focally positive
in low-grade endometrial stromal sarcoma.
Myxoid leiomyosarcoma. The spindle morphology with variable myxoid matrix characteristic of most high-grade endometrial stromal
sarcomas, particularly those harboring ZC3H7B::
BCOR fusion, share significant morphologic over-
lap with myxoid leiomyosarcoma. ZC3H7B::
BCOR fusion-positive tumors often show at least
focal CD10 expression and most lack myogenic
differentiation by immunohistochemistry. Among
tumors that demonstrate myogenic differentiation
by immunohistochemistry, only focal SMA
and/or h-caldesmon staining is seen while desmin
expression is typically absent. Thus, high-grade
endometrial stromal sarcoma should be considered in any myxoid uterine sarcoma lacking
desmin expression.
Adenosarcoma with sarcomatous over-
growth. Rare high-grade endometrial stromal sar-
comas may display entrapped glands mimicking
adenosarcoma with sarcomatous overgrowth;
however, phyllodes growth and periglandular
stromal condensation are absent in high-grade
endometrial stromal sarcoma. Pan-Trk expression
secondary to NTRK3 mRNA upregulation is seen
in most high-grade endometrial stromal sarcomas
with YWHAE and BCOR genetic abnormalities.
Undifferentiated Uterine Sarcoma
Synonyms
Undifferentiated endometrial sarcoma (not
recommended).
Definition
Undifferentiated uterine sarcoma is a malignant
mesenchymal tumor lacking evidence of cell
differentiation.
Clinical Features
• Incidence
Undifferentiated uterine sarcoma is rare.
• Site
Undifferentiated uterine sarcomas may involve
the endometrium and/or myometrium.
• Treatment
Patients with suspected uterus-confined
undifferentiated uterine sarcoma should
undergo hysterectomy with or without bilateral
salpingo-oophorectomy. Data on the clinical
management of extrauterine undifferentiated
uterine sarcoma is limited. Surgical staging
and cytoreduction may be offered for patients
without extra-abdominal metastatic disease.
Medical management of undifferentiated uterine sarcoma is extrapolated from treatment
approaches in metastatic or recurrent
leiomyosarcoma.
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Prognosis
Prognosis is poor. ER and/or PR expression
correlates with improved overall survival
(Binzer-Panchal et al. 2019; Hardell et al.
2017). Expression of genes related to extracellu-
lar matrix and mitotic index of at least 25 MF/10
HPF are associated with decreased overall and
5 year survival, respectively (Binzer-Panchal
et al. 2019;Gremeletal.2015;Hardell
et al. 2017).
Macroscopy
Undifferentiated uterine sarcoma is a large polypoid or intramural fleshy mass often associated
with hemorrhage and necrosis.
Microscopy
Undifferentiated uterine sarcoma consists of
circumscribed or infiltrative sheets of epithelioid
and/or spindled cells showing nuclear uniformity
or pleomorphism (Fig. 17). SMARCA4-deficient
tumors exhibit dyshesive epithelioid/rhabdoid
cells and myxoid matrix (Kolin et al. 2018).
Some pleomorphic tumors have foci of endometrial stromal sarcoma or fibrosarcoma. Brisk
mitotic activity, lymphovasc ular invasion, and
tumor necrosis are common.
Immunophenotype
Undifferentiated uterine sarcomas may express
ER, PR, and diffuse cyclin D1 or BCOR
(Binzer-Panchal et al. 2019; Gremel et al. 2015;
Kurihara et al. 2010). Tumors may also express
p16 and p53 (Gremel et al. 2015).
SMARCA4-deficient sarcomas show loss of
SMARCA4 expression and lack epithelial
markers (Kolin et al. 2018).
Molecular Features
Undifferentiated uterine sarcomas show extracellular matrix, leiomyosarcoma-like, developmental,
and low proliferation RNA expression profiles,
extensive gains and losses or diploidy with low
copy number variation (Binzer-Panchal et al.
2019).AsubsetoftumorsharborsSMARCA4
mutations (Kolin et al. 2018). YWHAE, JAZF1,
and NTRK rearrangements may underpin rare pleomorphic sarcomas lacking histologic features of
endometrial stromal sarcoma or fibrosarcoma-like
uterine sarcoma (Chiang et al. 2017, 2018;Cotzia
et al. 2019; Croce et al. 2013; Kurihara et al. 2008;
Li et al. 2007).
Differential Diagnosis
High-grade endometrial stromal sarcoma. Highgrade endometrial stromal sarcomas generally
demonstrate uniform moderate atypia in contrast
to undifferentiated pleomorphic sarcomas. Fusion
testing is often needed to distinguish high-grade
endometrial stromal sarcomas and undifferentiated
sarcoma with cytologic uniformity.
Carcinosarcoma and adenosarcoma with sar-
comatous overgrowth. Undifferentiated uterine
sarcoma lacks the epithelial component characteristic of these tumors. Extensive tissue sampling is
over required to exclude these two entities.
Leiomyosarcoma and rhabdomyosarcoma.
Undifferentiated uterine sarcoma lacks smooth
muscle and skeletal differentiation.
Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 17 Undifferentiated uterine sarcoma. Markedly
pleomorphic cells form sheets and are associated with brisk
mitotic activity
Uterine Tumor Resembling Ovarian Sex
Cord Tumor
Definition
Uterine tumor resembling ovarian sex cord tumor
(UTROSCT) is a uterine mesenchymal neoplasm
that demonstrates histologic patterns resembling
ovarian sex cord tumors and lacks an endometrial
stromal component.
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Clinical Features
• Incidence
Tumors are rare.
• Age
The median patient age is 50 (range, 12–86)
years (Bennett et al. 2020b; Goebel et al. 2020;
Lee et al. 2019; Moore and McCluggage
2017).
• Site
Tumors involve the uterine corpus.
• Treatment
Information on treatment approaches in
patients with UTROSCT is limited due to
the rarity of this tumor type. Hysterectomy
with or without bilateral salpingo-
oophorectomy is usually undertaken. For
recurrent disease, surgical resection may be
performed. Radiation therapy for localized
disease or systemic therapy for metastatic
disease may be considered if the recurrence
is not operable.
• Outcome
UTROSCT is considered to have low malignant potential . Most tumors are benign, but
malignant cases have been reported.
Macroscopy
Tumors may be intramural, submucosal, or subserosal. Some UTROSCTs may be polypoid and
project into the endometrial cavity. They are often
well circumscribed with solid, yellow or tan cut
surfaces.
Microscopy
UTROSCTs may be circumscribed or infiltrative
into the adjacent myometrium. Histologic features
are often variable. Tumor cells may form sheets,
cords, trabeculae, nests, and/or tubules that may
appear sertoliform or retiform (Fig. 18). Multiple
architectural patterns are often present. Cells may
be spindled and/or epithelioid. Nuclei are usually
round to oval and uniform with inconspicuous or
Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 18 Uterine tumor resembling ovarian sex cord
tumor. Cytologically uniform cells form (a) nests, cords,
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rare tubules, (b) trabeculae, (c) sheets, and/or (d) retiform
and gland-like structures
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prominent nucleoli and can be grooved. Cytoplasm is scant to abundant and can be pale and
foamy or eosinophilic, sometimes imparting a
rhabdoid appearance. Mitotic activity is variable.
Stromal hyalinization, myxoid change, or edema
may be present. Lymphovascular invasion is
occasionally seen.
Immunophenotype
Tumors a re polyphenoty pi c and demonstrate
variable expression of sex cord (inhibin,
calretinin, FOXL2, SF1, melan-A, CD99,
WT1, and CD56), epithelial (AE1/AE3 and
EMA), smooth muscle (desmin, SMA, and
h-caldesmon), and hormone receptor (ER and
PR) markers, as well as CD10 (Hurrell and
McCluggage 2007).
Molecular Features
UTROSCTs may harbor ESR1 and GREB1
rearrangements with a variety of fusion partners,
including NCOA1, NCOA2, NCOA3, CTNNB1,
NR4A3,andSS18 (Croce et al. 2019; Dickson
et al. 2019; Goebel et al. 2020; Lee et al. 2019).
Despite histologic resemblance to endometrial stromal and ovarian sex cord stromal tumors,
UTROSCTs lack JAZF1::SUZ12 fusion, FOXL2
mutations, and DICER1 genetic alterations
(Chiang et al. 2015; Croce et al. 2019; Staats
et al. 2009).
Differential Diagnosis
Low-grade endometrial stromal sarcoma with
sex cord-like differentiation. While sex
cord-like differentiation may occur in low-grade
endometrial stromal sarcoma, these tumors often
demonstrate areas of conventional low -grade end ometrial stromal sarcoma morphology. The presence
of ESR1 or GREB1 rearrangements favors
UTROSCT, while the presence of JAZF1
rearrangements favors low-grade endometrial stromal sarcoma.
Adenosarcoma with sex cord-like differentiation. Some adenosarcomas demonstrate extensive
sex cord-like differentiation. In such cases, extensive sampling is recommended and may uncover
foci of phyllodes growth and periglandular stromal condensation that are characteristic of
adenosarcoma. ESR1 rearrangements have been
detected in adenosarcomas with and without sex
cord-differentiation and shoul d be interpreted in
the correct histologic context.
Endometrioid carcinoma with sex cord-like
growth. Endometrioid carcinomas with sex cord-
like growth almost always demonstrate glandular
areas with typical endometrioid morphology.
Epithelioid smooth muscle tumor. Cords and
trabeculae can be seen in epithelioid smooth muscle tum ors. However, epithelioid smooth muscle
tumors lack expression of sex cord markers by
immunohistochemistry.
Perivascular Epithelioid Cell Tumor
(PEComa)
Definition
Perivascular epithelioid cell tumor (PEComa) is a
tumor of perivascular epithelioid differentiation
that expresses melanocytic and myogenic markers
and belongs in the PEC family of tumors, including angiomyolipoma, lymphangiomyomatosis,
and clear cell tumors of the lung and pancreas.
Clinical Features
• Incidence
This tumor is rare.
• Age
The median age is 54 (range, 41–71) years
(Agaram et al. 2015; Bennett et al. 2018;
Schoolmeester et al. 2014, 2015).
• Site
Tumors may be intramural or subserosal.
• Treatment
Information on treatment approaches in
patients with uterine PEComa is limited due
to the rarity o f this tumor type. Hysterectomy
with or without bilateral salpingo-
oophorectomy is usually undertaken. mTOR
inhibition may show benefit in patients with
TSC1/TSC2 mutations.
Prognosis
Based on the most recent WHO classification of
gynecologic tumors, at least three of the following
features are associated with malignant behavior:
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Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 19 Perivascular epithelioid cell tumor
(PEComa). Tumors may be composed of (a) bland
tumor size 5 cm, high nuclear grade, necrosis,
and vascular invasion. Any tumor displaying
fewer than three of the above features is considered of uncertain malignant potential.
Macroscopy
Uterine PEComas are well circumscribed or infiltrative and may demonstrate hemorrhage and/or
necrosis.
Microscopy
PEComa is composed of epithelioid and/or spindled cells with clear to eosinophilic granular cytoplasm (Fig. 19). Multinucleated cells, ce lls with
lipid-rich or rhabdoid cytoplasm, and stromal
hyalinization are often present. Tumors may
have infiltrative, permeative, or pushing borders.
Melanin pigment may be seen.
Immunophenotype
Uterine PEComas are variably positive for
melanocytic (HMB45, melan-A, S100 , MITF,
and tyrosinase) and smooth musc le (desmin,
SMA, and h-caldesmon) markers (Bennett
et al. 2018; Schoolmeester e t al. 2014).
HMB45 and melan-A are more frequently
expressed than S100, MITF, and tyrosinase.
Cathepsin K is frequently positive (Bennett
et al. 20 18; Rao et al. 2013; Va lencia-Guerrero
et al. 2020). Some tumors may be positive for
keratins, ER, and PR. TFE3 fusion-positive
epithelioid cells with abundant clear cytoplasm or (b)
large polygonal cells with pleomorphic nuclei and abundant eosinophilic granular and vacuolated cytoplasm
PEComas are diffusely and str ongly positive
for TFE3, HMB45, and cathepsin K
(Schoolmeester et al. 20 15).
Molecular Features
Tumors may harbor TSC1/TSC2 mutations or
rearrangements involving TFE3 or RAD51B.
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Differential Diagnosis
Epithelioid smooth muscle tumor. Epithelioid
smooth muscle tumors and PEComas have epithelioid and spindled components and both share
variable myomelanocytic differentiation. Clear to
pale eosinophilic granular cytoplasm, round to
oval nuclei, and prominent capillary network.
Malignant melanoma. While HMB45
melan-A, and MiTF staining may be seen in
both uterine PEComa and malignant melanoma,
the latter is also frequently positive for SOX10
and S100 and is negative for myogenic markers.
Inflammatory Myofibroblastic Tumor
Synonyms
Inflammatory pseudotumor (not recommended).
Definition
Inflammatory myofibroblastic tumor (IMT) is a
mesenchymal neoplasm of intermediate biologic
potential that is composed of myofibroblastic and
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fibroblastic spindle cells associated with a mixed
inflammatory infiltrate.
Clinical Features
• Incidence
Uterine IMTs are rare.
• Age
Uterine IMT typically affects women of reproductive age with a median of 37 (range, 8–78)
years (Bennett et al. 2017a, 2020a; Chiang
2021; Gilks et al. 1987; Haimes et al. 2017;
Mohammad et al. 2018; Parra-Herran et al.
2015; Rabban et al. 2005).
• Site
IMT can occur in any anatomic location and is
Mesenchymal Tumors, Pathology of the Uterine Corpus, Fig. 20 Inflammatory myofibroblastic tumor (IMT).
Monomorphic spindle cells are associated with a mixed
inflammatory infiltrate
most frequent in the abdominal soft tissues. In
decreasing order, it can also involve the lung,
mediastinum, head, and neck, as well as the
gastrointestinal, genitourinary, and gynecologic tracts. The uterus is the most common
site among female genital tract tumors. Lesions
involving the corpus may be submucosal,
intramural, or subserosal.
• Treatment
growth or intersecting fascicles of spindle cells
with variable myxoid and/or collagenous stroma
and inflammatory cells (Fig. 20). The hyalinized
pattern consists of rare spindle cells and inflammatory cells embedded in collagenous stroma. Cytologic atypia is often mild to moderate and rarely
severe. Mitotic activity is variable. Deciduoid morphology may be seen in the setting of pregnancy.
Patients with recurrent tumors harboring ALK
rearrangements may benefit from tyrosine
kinase inhibitors (Gambacorti-Passerini et al.
2018; Mosse et al. 2017).
• Outcome
Most uterine IMTs are benign, but a subset of
tumors may have extrauterine spread and/or
recur (Bennett et al. 2017a; Devereaux et al.
2019; Kushnir et al. 2013).
Immunophenotype
IMTs show variable expression of CD10, desmin,
SMA, and h-caldesmon, and are negative for keratins, S100, CD34, and CD117 (Bennett et al.
2017a; Parra-Herran et al. 2015). Strong and dif-
fuse p16 expression is uncommon, and p53
staining is heterogeneous (Bennett et al. 2020a;
Schaefer et al. 2017). Tumors may be positive for
IFITM1 and transgelin (Bennett et al. 2020a).
Macroscopy
IMTs may be circumscribed or infiltrative.
Tumors may be soft and gelatinous or firm and
whorled. Hemorrhage and necrosis may be
present.
Limited BCOR staining may be observed
(Bennett et al. 2020a). ALK staining is seen in
most uterine IMT and is highly specific for ALK
fusion; staining patterns, however, vary in intensity and distribution depending on the ALK fusion
partner (Bennett et al. 2017a; Haimes et al. 2017;
Microscopy
IMTs consist of one or more of the following histologic patterns: myxoid, fascicular, and hyalinized. In
Mohammad et al. 2018; Pickett et al. 2017). ROS
expression may be seen in less common IMTs
harboring ROS1 fusion (Hornick et al. 2015).
the myxoid pattern, spindle cells are associated with
abundant myxoid matrix, numerous blood vessels,
and a mixed inflammatory infiltrate composed of
plasma cells, lymphocytes, and eosinophils. The
fascicular pattern is characterized by storiform
Molecular Features
Most uterine IMTs harbor ALK rearrangem ent
with variety of fusion partners, including
IGFBP5, TIMP3, THBS1, FN1, TNS1, DES,
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