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Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus 87
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the endometrium or ovary, the tumors exhibit other
features that put the patient in a high-risk group
requiring adjuvant therapy. Independent stage
1 synchronous endometrioid carcinomas of the
endometrium and ovary has a good prognosis.
Serosal involvement occurs typically in the
tumors that exhibit deep, full thickness
myometrial invasion. Extension of the tumor
cells through the visceral peritoneum indicates
poor overall prognosis (Ashman et al. 2001).
Myometrial invasion plays an important role in
determining the prognosis of endometrial carcinoma. The extent of invasion is measured from
the interface of the endometrium and myometrium
to the point of maximal myometrial invasion. The
typical endometrial-myometrial junction, however, is generally irregular making accurate
measurement challenging (Ali et al. 2007). This
measurement is expressed as a percentage or listed
as an exact measurement. Myometrial invasion is
frequently overestimated in cases where the bulk
of the tumor or the entirety of the tumor is exophytic and protrudes into the endometrial cavity.
In such instances, the tumor thickness should not
be interpreted as myometrial invasion.
A multitude of patterns may exist with single
gland invasion being the most common.
(b) Tumors may show a broad pushing front.
(c) The microcystic elongated and fragmented
(abbreviated as the MELF pattern) is relatively infrequent; however, it is important to
be aware of this particular type since it is
frequently associated with lymph vascular
invasion and subsequent lymph node metastasis. The malignant glands show low cuboidal to attenuated epithelium, incomplete to
abortive glands, with associated inflammatory
infiltrate and stromal changes (Figs. 5 and 6).
Anytime a MELF pattern of invasion is identified in a hysterectomy, it is of prudent to
scrutinize the leading edge of the tumor for
E
(a) The neoplastic glands are observed infiltrating
the myometrium often with surrounding
desmoplasia (Fig. 4).
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 4 Infiltrative pattern of
myometrial invasion
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 5 Microcystic elongated
and fragmented pattern of invasion (MELF)
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 6 MELF pattern. High
power view of malignant glands with attenuated epithelium and inflammatory stromal response
88 Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus
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vascular invasion and the lymph nodes at
higher magnification. Presence of histiocytoid
tumor cells within vascular channels can be
confirmed by immunoperoxidase stains.
(d) Assessment of myometrial invasion occ urring
in a background of adenomyosis.
The recognition of well demarcated rounded
nests of adenomyosis, the lack of desmoplastic
response in the myometrium, the presence of
endometrial stroma around adenomyotic foci
and finding neighboring foci of uninvolved
adenomyosis are features helpful in making
the distinction. When a small focus of malignant glands is found deep in the myometrium
with adjacent adenomyosis, the depth of invasion should be measured from the nearest overlying focus of adenomyosis. Tumors involving
adenomyosis are more likely to progress to true
myometrial invasion (Ismil et al. 2007;Hanley
et al. 2010).
The typical endometrial-myometrial junction
is uneven, and not a well demarcated boundary,
making the assessment of myometrial invasion
challenging. Myometrial invasion plays an important role in staging of endometrial carcinoma, and
therefore accurate assessment is crucial. The
extent of invasion is measured from the interface
of the endometrium between the myometrium to
the maximal depth of invasion. This measurement
is expressed as a percentage or listed as an exact
measurement, however, which may not be determined with certainty in challenging cases.
The presence and extent of angiolymphatic
invasion in endometrial carcinoma carries prognostic significance (Stefanson et al. 2004). In the
vast majority of cases, lymph-vascular space invasion can be readily identified with established
histologic parameters including tumor cells
conforming to the shape of the vessel, degenerative changes with the tumor cells, and the presence of a perivascular inflammatory response.
With advances in surgical techniques such as laparoscopic and robotic procedures, displacement of
tumor emboli has been observed increasingly.
This likely results from uterine manipulation during surgery itself and subsequently by handling of
the pathologists. Adequate formalin fixation for
several hours has been found to be optimal in
reducing this artifact.
The regional lymph node status is of paramount importance in determining clinical outcomes in patients with endometrial carcinoma
(Chan et al. 2007). Pelvic lymph node metastases
ordinarily occur before para-aortic lymph nodes
and surgically alter the risk of para-aortic lymph
node involvement, increasing risk to approximately 50% (Chi et al. 2008). The size of the
metastatic foci impacts prognosis with macrometastasis (>2 mm) observed to have worse outcomes than micrometastasis. The role of isolated
tumor cells is less clear at this time.
Sentinel lymph node (SLN) assessment is
increasingly becoming standard practice in patients
undergoing surgery for endometrial carcinoma.
SLN mapping performed intraoperatively is
followed by ultra-staging of lymph nodes in surgical
pathology using serial sections and the use of immunohistochemistry (pankeratin) to detect low volume
disease. The advantage of this procedure is signifi-
cant reduction in morbidity associated with lymph
node dissection in patients who are stratified as low
risk for metastasis based on clinical, histologic and
imaging parameters.
Metastasis to pelvic and para-aortic lymph
nodes is categorized as stage IIIc disease, which
decreases the disease free 5-year survival to 36%.
Although peritoneal washings have been withdrawn as a staging parameter in the current FIGO
staging system, data shows that positive peritoneal washings are associated with an increased
risk of recurrence and serve as an independent
risk factor (Garg et al. 2013). Up to 20% of all
endometrial carcinoma cases will have positive
cytologic studies with a higher frequency seen in
robot assisted procedures.
Macroscopy
The gross appearance of endometrial carcinoma
varies from mildly thickened, heaped up mucosa
that lines the endometrial cavity to bulky exophytic mass-like lesion with rare tumors presenting as nodules. The tumor is frequently soft
and friable on cut surface but can have a fleshy or
gritty consistency with necrosis. The uterus may
appear large and boggy in some cases, however,
Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus 89
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and may be normal in size. The size of endometrial carcinoma is difficult to discern with the
naked eye since a discrete mass is not frequently
visible. Additionally, tumors may be primarily
situated in the lower uterine segment, as seen in
patients with Lynch syndrome and microsatellite
instability, often clinically presenting as primary
cervical tumors. Gross examination of endometrial neoplasms is useful in determining the presence and extent of myometrial invasion, although
concomitant adenomyosis can make the distinction difficult.
E
Microscopy
The classic histomorphology of endometrioid
adenocarcinoma is that of glandular, cribr iform,
and labyrinthine patterns. Termed “ endometrioid”
due to its semblance to proliferative endometrium.
The tumor cells are arranged around smooth glandular lumina and exhibit nuclei ranging from tall
columnar nuclei with pseudostratification and
hyperchromasia (grade 1) to grade 2 ovoid/round
vesicular nuclei with occasional nucleoli and open
chromatin pattern. Grade 3 nuclei display conspicuous nucleoli, nuclear pleomorphism with
occasional bizarre shapes and brisk mitotic activity. Striking nuclear atypia can be used to increase
the FIGO grade. Stromal accumulation of foamy
macrophages is frequently observed in the endometrioid histotype of endometrial carcinoma.
Although not pathognomonic, this histologic feature is helpful in distinguishing endometrial
vs. endocervical primary malignancies especially
in biopsy and curettage specimens.
Endometrioid carcinomas are typically graded
by the International Federation of Gynecology
and Oncology (FIGO) system into grade 1, grade
2, and grade 3 depending upon the amount of nonsquamous solid components present in the tumor.
Tumors with less than 5% of solid growth are
graded as 1, a solid pattern comprising more
than 5% (Fig. 7 ) and less than 50% as FIGO
2 (Fig. 8) and greater than 50% non-squamous
solid growth as FIGO grade 3 (Fig. 9). Although
not freque ntly encountered, significant nuclear
atypia in otherwise FIGO 1 and 2 grade tumors,
when present, can be used as a parameter to
increase the FIGO grade by one. A glandular
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 7 Well-differentiated endo-
metrioid adenocarcinoma
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 8 Endometrioid adenocar-
cinoma, FIGO grade 2
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 9 Endometrioid adenocar-
cinoma with >50% solid growth, FIGO grade 3
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tumor, however, with discordant high-grade
cytology, should always prompt the consideration
of a serous carcinoma that would have a vastly
different clinical course, treatment, and outcome.
Although the FIGO grade is typically used in
daily sign out of endometrioid and mucinous carcinomas (Zaino et al. 1995), recent studies have
proposed the use of binary system which categorizes FIGO 1 and FIGO2 endometrioid carcinomas into a low-grade group and endometrioid
FIGO 3 into high grade endometrial carcinomas
(Conlon et al. 2014; Bosse et al. 2018).
Endometrioid Carcinoma with Squamous
Differentiation
Endometrioid carcinoma with squamous differentiation is the most common histomorphologic variant of endometrioid adenocarcinoma, seen in up
to one quarter of all endometrioid tumors. The
histopathology is characterized by nests of nonkeratinizing (morular) or keratinizing squamous
cells with eosinophilic to glycogenated cytoplasm, intercellular bridges, crisp cytoplasmic
borders, and small, hyperchromatic nuclei
(Fig. 10). The areas of squamous differentiation
are admixed with otherwise typical malignant
endometrial glandular epithelium. In general, the
presence of squamous morular metaplasia is a
useful finding in the diagnosis of endometrioid
adenocarcinoma and can be used as a reliable
feature to confirm an endometrioid histotype in
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 10 Endometrial adenocar-
cinoma with prominent squamous differentiation
challenging cases. Tumors with a prominent squamous differentiation can be associated with keratin granulomas involving the peritoneum or
ovarian surface secondary to transtubal spread;
however, their presence doe s not alter prognosis.
Keratin granulomas are composed of keratin
aggregates, histiocytes, foreign body giant cells,
and nonviable squamous cells. Viable tumor cells
should be absent. At lower magnification, these
squamous nests can appear as solid foci of tumor
cells. It is important to evaluate these areas at a
higher magnification to avoid overestimation of
the solid component for the purposes of FIGO
grading. Erroneous classification of these tumors
as having greater than 50% of solid components
can result in unnecessary adjuvant treatment of
these patients. As a general rule, the cytology of
the squamous nests is usually similar to the adjacent glandular tumor cells. The prognosis of endometrioid carcinomas with squamous
differentiation is that of low-grade endometrial
carcinomas.
Endometrioid Carcinoma with Villoglandular
Pattern
Endometrioid adenocarcinomas can show prominent filiform configuration in 15–30% of all endometrioid carcinomas and this specific histotype is
termed villoglandular endometrioid adenocarcinoma (VGEC). The distinctive papillary configuration, defined by slender fronds lined by
fibrovascular cores, is mostly observed in the
superficial portions of the tumor with deeper
myoinvasive aspects of the tumor exhibiting conventional endometrioid morphology (Zaino et al.
1998). The tumor cells have pseudostratified
nuclei situated perpendicular to the basement
membrane (Fig. 11). These tumors lack the
high-grade cytology observed in high grade endometrial carcinomas like serous and clear cell carcinomas. Occasionally the nuclei may undergo
degenerative changes and become hyperchromatic with nuclear pleomorphism mimicking
serous carcinoma. In such diagnostically challenging cases, immunohistochemical staining
can be utilized for accurate histotyping.
Villoglandular endometrioid adenocarcinomas
behave like low grade endometrioid
Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus 91
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E
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 11 Villoglandular endo-
metrioid carcinoma with slender papillae
adenocarcinomas with an indolent course for the
most part. VGEC that exhibit deep myometrial
invasion, however, have been associated with
angiolymphatic invasion, subsequent lymph node
metastases, and overall worse outcome compared
to conventional endometrioid myoinvasive tumors.
Endometrioid Carcinoma with Small
Non-villous Papillae
Another variant of endometrioid carcinoma with
a papillary pattern is the endometrioid carcinoma
with smal l non-villous papillae (SNVP). The
typical configuration of the tumor is that of
micropapillae that are somewhat bulbous, associated cellular tufts and buds. Occasional
detached cells and hobnail cells may also be
observed. The tumor cells have mild to moderate
cytologic atypia with round to polygonal cells
and abundant eosinophilic cytoplasm suggestive
of squamous differentiation. Well-developed
squamous metaplasia is noted in greater than
50% of tumors. At low magnification, the histology may resemble that of a serous carcinoma;
however, high-grade nuclear features should be
absent (Fig. 12).
Endometrioid Carcinoma with Microglandular
Pattern
Endometrioid carcinoma with a microglandular
carcinoma is relatively uncommon, tumor defined
by a back-to-back configuration of small glands
with intraluminal secretions, low grade cytologic
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 12 Endometrial carcinoma
with small non-villous papillae. Tumor cells exhibit eosinophilic cytoplasm and low grade cytologic atypia
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 13 Endometrial carcinoma
with microglandular pattern
atypia, and associated neutrophils (Fig. 13). Typically, an otherwise conventional endometrioid
component is also identified (Young and Scully
1992). This specific morphologic subtype is
important to recognize since the histology mimics
microglandular hyperplasia of the cervix, a purely
benign endocervical lesion seen most commonly
in the premenopausal women on oral contraceptives (Zaloudek et al. 1997). In contrast microglandular endometrioid adenocarcinoma occurs
largely in postmenopausal women. The age of
the patient, clinical presentation (frequently
abnormal uterine bleeding), the finding of an associated endometrioid pattern, nuclear atypia, and
92 Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus
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an increased proliferation index argue against
microglandular hyperplasia of the cervix. Additionally immunophenotypically endometrioid
adenocarcinomas express ER, PR, and vimentin
while endocervical microglandular hyperplasia is
typically negative for these markers (Checmareva
et al. 2008). Caution must therefore be exercised
in any postmenopausal patient in which the diagnosis of cervi cal microglandular hyperplasia is
considered. Interestingly, this variant of endometrioid adenocarcinoma has been shown to
have underlying KRAS mutations (Hong et al.
2015).
Endometrioid Carcinoma with Secretory
Features
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 14 Endometrial carcinoma
with secretory features. The tumor cells show subnuclear
vacuoles resembling early secretory phase endometrium
A relatively uncommon variant of endometrioid
adenocarcinoma characterized by discrete subnuclear and occasionall y supranuclear vacuoles
within the tumor cells is the secretory variant of
endometrioid adenocarcinoma (Fig. 14). Resembling physiologic early secretory phase, the neoplastic cells impart a clear cell appearance at low
power assessment raising concern for a clear cell
carcinoma. Careful examination of the tumor cells
at higher magnification shows relatively bland
mostly round to ovoid nuclei without conspicuous
nucleoli unlike clear cell carcinoma tumor cells
which almost universally exhibit a higher-grade
cytology.
Endometrioid Carcinoma with Spindled
Features
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 15 Endometrial carcinoma
with spindled features. The cytologic features of both glandular and spindled components are similar
This morphologic subtype of endometrioid carcinoma is one of the two variants of endometrioid
carcinoma that can simulate carcinosarcoma. As
the name implies, this particular histotype of
endometrioid carcinoma is characterized by a
prominent spindle cell appearance of tumor cells
that merges imperceptibly with an otherwise conventional endometrioid glandular carcinoma
(Fig. 15). The nuclei of the spindled tumor
cells are qualitatively identical to the present in
the adjoining glandular component. Unlike
MMMTs, these tumors have prognosis similar to
FIGO I-II endometrioid carcinomas, and therefore
recognition of this pattern is of utmost significance for optimal treatment.
Corded and Hyalinized Endometrioid
Carcinoma (CHEC)
A histologic variant first described by Murray
et al., the corded and hyalinized variant of endometrioid adenocarcinoma (CHEC) is important to
recognize since the peculiar histomorphology
appears biphasic, especially at low magnification,
and the tumor may be mistaken for a carcinosarcoma. The tumor cells of CHEC exhibit nuclei
morphologically similar to those of low grade
endometrioid carcinoma with ovoid vesicular
nuclei, occasional nucleoli, and scattered mitotic
figures. The stroma of this tumor is distinctive
with pale-pink, plump polygonal stromal cells
Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus 93
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E
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 16 Corded and hyalinized
endometrioid carcinoma (CHEC)
that are epithelioid, mimicking an “osteoid” pattern (Fig. 16). These stromal cells, however, lack
the high-grade nuclear features including nuclear
hyperchromasia, pleomorphism, and brisk mitotic
activity that is characteristic of the sarcomatous
component of a carcinosarcoma. To make the
distinction from carcinosarcoma even more difficult, rarely, foci of osseous and/or chondroid
metaplasia may also be present within the stromal
component of CHEC raising the differential diagnosis of a heterologous component (osteosarcoma
and chondrosarcoma) of a carcinosarcoma.
Again, the distinctive high grade cytologic atypia
is absent in areas of osseous/chondroid metaplasia,
with the nuclei appearing morphologically similar to
the endometrioid glandular components. In cases
where the cytologic atypia is concerning for a
higher-grade tumor , immunoperoxidase staining
with p53 stain can be extremely useful demonstrating wild type staining pattern in CHEC and
exhibiting a mutated pattern in both the carcinoma
and sarcoma components of a carcinosarcoma. The
prognosis of CHEC is that of a low grade endometrioid adenocarcinoma with most patients requiring no adjuvant therapy after hysterectomy, unlike
carcinosarcoma which due to its aggressive behavior requires further treatment in most patients.
Endometrioid Carcinoma with Mucinous
Differentiation
Mucinous differentiatio n in endometrioid adenocar cinomas is not uncommon with intracytoplasmic
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 17 Mucinous carcinoma.
Greater than 50% of tumor cells show intracytoplasmic
mucin
mucin often present in otherwise conventional endometrioid carcinoma, Pure, mucinous carcinoma is
defined as intracytoplasmic mucin present in >50%
of tumor cells (Fujiwara and Longacre 2011). The
designation is of less significance since these neoplasms essentially behave like endometrioid carcinoma with similar gross and microscopic features.
Rarely extravasated mucin may be present on gross
examination of the tumor. Microscopically conve ntional endometrioid adenocarcinoma with glandular,
cribriform, and villoglandular patterns is observed
with prominent intracellular mucin (Fig. 17). The
nuclei are relatively bland in most cases resembling
nuclei observed in FIGO grade 1 tumors. Microglandular patterns may occasionally be seen with
mucinous differentiation resembling microglandular
hyperplasia of the cervix (Hussein et al. 2012).
Endometrioid Carcinoma with Sertoliform
Pattern
An uncommon subtype of endometrioid carcinoma, the sertoliform pattern shows prominent
tubules that may be hollow or solid as well as a
cord-like arrangement (Eichhorn et al. 1996).
These tubules and/or cords are lined by columnar
cells with a modest amount of clear to eosinophilic cytoplasm (Fig. 18). A component of
usual endometrioid histology is almost always
identified that serves as an important diagnostic
clue (Murray et al. 2005).
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Mismatch repair protein deficiency (MMR) is
seen either sporadically or as a part of the autosomal dominant Lynch syndrome (LS). Women with
Lynch syn drom e have a 60–70% increased risk of
developing endometrial carcinoma (Lynch et al.
1966). Additionally, endometrial carcinoma may
often present as the “sentinel” carcinoma in these
patients.Immunohistochemistry for MMR proteins
is being widely utilized to detect the loss of expression of protein in endometrial carcinoma. Loss of
MSH2 and MSH6, and isolated PMS2 protein loss
is highly suggestive of Lynch syndrome. Microsat-
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 18 Endometrioid carci-
noma with sertoliform pattern
ellite instability testing (MSI) can be used as an
alternative or adjunct to immunohistochemistry.
Loss of MLH1 and PMS2 is the most common
pattern of abnormal MMR profile with the majority
Immunophenotype
of tumors exhibiting loss of MLH1 due to hypermethylation. Tumors with loss of MLH1 and
Low grade endometrioid adenocarcinomas are
characterized by strong, diffuse expression of
estrogen receptor (ER), and progesterone receptor
(PR). p53 is typically wild type. Unlike the low
grade endometrioid adenocarcinomas, FIGO
3 endometrioid carcinomas can lack ER and PR
expression in up to 70% of cases and show aberrant p53 expression which is often problematic in
distinguishing these tumors from high grade carcinomas including serous and clear cell types.
AMACR expression has been observed in endometrioid carcinomas with squamous differentiation and clear cell features, and therefore should
not be relied as a marker of clear cell histotype in
the absence of traditional clear cell carcinoma
histomorphologic features.
PMS2 should be reflexed to hypermethylation testing of MLH1 gene. If hypermethylation is not
detected, further germline testing must be pursued
to look for germline mutations (Battle et al. 2014;
Mills et al. 2014;Buzaetal.2016). Identification of
these patients is of paramount importance since it
can lead to screening for other tumors that the
patient and the patient’s family members are pre-
disposed to. Risk reducing hysterectomy has been
proposed as a measure to reduce the incidence of
endometrial carcinoma in patients known to have
the germline mutation and do not desire fertility
(Diaz-Padilla et al. 2013).
Endometrial carcinomas with the POLE mutations show high grade histology with prominent
tumor infiltrating lymphocytes. Despite the highgrade morphology, this group of tumors tends to
have a good prognosis (Hussein et al. 2015;
Molecular Features
Bakhsh et al. 2016). The recognition of this entity
is helpful since it can reduce aggressive therapy in
TCGA defined endometrial carcinomas into four
distinct groups: (1) hypermutated associated with
endometrioid histology, (2) ultramutated, POLE
(polymerase-epsilon) group characterized by high
grade histology with better overall survival,
(3) copy number low group characterized by
endometrioid morphology, and (4) copy number
high group with p53 mutations and serous carcinoma being the prototype (Cancer Genome Atlas
Research Network et al. 2013).
patients due to improved outcomes; however, currently detection is limited in clinical practice due
to the availability of molecular testing.
PTEN mutations play an important role in the
development of endometrial carcinoma of endometrioid histology. While the vast majority of
tumors have sporadic loss, germline mutations
characterize Cowden syndrome with female
patients at risk for endometrial, breast, and colorectal carcinoma.
Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus 95
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Differential Diagnosis
Endometrial carcinoma with squamous differentiation demonstrates glycogenated squamous tumor
cells with clear cytoplasm. This pattern can be
confused with clear cell carcinoma; however, the
typical high-grade cytology of clear cell carcinoma is lacking in these areas. As a general rule,
the cytology of the squamous nests is usually
similar to the adjacent glandular tumor cells. The
prognosis of endometrioid carcinomas with squamous differentiation is that of low-grade endometrial carcinomas.
Endometrioid adenocarcinomas with
villoglandular pattern show strong, diffuse ER
and PR expression, negative WT-1 and a wildtype p53 in contrast to the aberrant p53 expression
almost always present in serous carcinoma and
can be seen in up to 50% of clear cell carcinomas.
WT-1 staining is observed in approxi mately one
third of endometrial serous carcinomas, and when
present can be helpful in distinguishing these
tumors from both endome trioid and clear cell
carcinomas that are typically negative for WT-1.
Differentiating corded and hyalinized endometrial carcinoma from carcinosarcoma is crucial
due to the differences in outcome of the two
tumor types. Tumors that demonstrate cytologic
atypia concerning for a higher-grade tumor,
immunoperoxidase staining with p53 stain can
be extremely useful demonstrating wild-type
staining pattern in CHEC and exhibiting a
mutated pattern in both the carcinoma and sarcoma components of a carcinosarcoma.
Another pattern of endometrial carcinoma that
can be used with carcinosarcoma is endometrioid
carcinoma with spindled features. Overt malignant cytology is absent in the spindled areas of
endometrioid carcinoma and is a key
distinguishing feature from the carcinosarcoma,
specifically the homologous type.
Endometrial carcinoma with microglandular
pattern can mimic endocervical glandular hyperplasia. These tumors typically arise in postmenopausal women and caution must therefore
be exercised in any postmenopausal patient in
which the diagnosis of cervical microglandular
hyperplasia is considered. These tumors will
exhibit mild to moderate cytologic atypia, arranged
in a small glandular pattern often with stromal
marcophages. Immature squamous metaplasia and
prominent subnuclear vacuoles seen in endocervical microglandular hyperplasia are absent.
Endometrial carcinomas with small nonvillous papillae may be confused with serous carcinoma of the endometrium especially at low
magnification due to the prominent papillary pattern. Judicious evaluation of the nuclear features
can aid in avoiding a misdiagnosis of serous carcinomas in these cases, since these tumors behave
like low grade endometrioid adenocarcinomas
(Garg and Soslow 2012). In contrast, serous carcinoma of the endometrium demonstrates a prominent papillary architecture with the polygonal,
relatively eosinophilic tumor cells characterized
by enlarged nuclei and prominent, often cherryred nucleoli. Numerous mitotic figures and often
increased apoptotic activity usually accompany
the high-grade nuclear features.
The immunophenotype of mutated p53, weak
to often negative ER and PR expression in serous
carcinoma can be very useful in differentiating the
two entities.
Endometrioid adenocarcinomas w ith
villoglandular pattern show strong, diffuse ER
and PR expression, negative WT-1, and a wildtype p53 in contrast to the aberrant p53 expression
almost always present in serous carcinoma and
can be seen in up to 50% of clear cell carcinomas.
WT-1 staining is observed in approximately onethird of endometrial serous carcinomas, and when
present can be helpful in distinguishing these
tumors from both endometrioid and clear cell
carcinomas that are typically negative for WT-1.
References and Further Reading
Ali, A., Black, D., & Soslow, R. A. (2007). Difficulties in
assessing the depth of myometrial invasion in endome-
trial carcinoma. International Journal of Gynecologi-
cal Pathology, 26,115–123.
Ashman, J. B., Connell, P. P., Yamanda, D., et al. (2001).
Outcome of endometrial carcinoma patients with
involvement of the uterine serosa. Gynecologic Oncol-
ogy, 82, 338.
Baak, J. P., Mutter, G. L., Robboy, S., et al. (2005a). The
molecular genetics and morphometry-based
E
96 Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus
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endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health
Organization classification system. Cancer, 103,
2304–2312.
Baak, J. P. A., van Diermen, B., Steinbakk, A., et al.
(2005b). Lack of PTEN expression in endometrial
intraepithelial neoplasia is correlated with cancer progression. Human Pathology, 36, 555–561.
Bakhsh, S., Kinloch, M., Hoang, L. N., et al. (2016).
Histopathological features of endometrial carcinomas
associated with POLE mutations: Implications for decisions about adjuvant therapy. Histopathology, 68,
916–924.
Battle, B. A., Bruegl, A. S., Daniels, M. S., et al. (2014).
Consequences of universal MSI/IHC in screening
endometrial cancer patients for Lynch syndrome. Gyne-
cologic Oncology, 134(2), 319–325.
Bokhman, J. V. (1983). Two pathogenetic types of endome-
trial carcinoma. Gynecologic Oncology, 15(1), 10–17.
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Bosse, T., Nout, R. A., McAlpine, J. N., et al. (2018). Molec-
ular classification of grade 3 endometrioid endometrial
cancers identifies distinct prognostic subgroups. The
American Journal of Surgical Pathology, 42,561–568.
Buza, N., Ziai, J., & Hui, P. (2016). Mismatch repair
deficiency testing in clinical practice. Expert Review
of Molecular Diagnostics, 16(5), 591–604.
Cancer Genome Atlas Research Network, Kandoth, C.,
Schultz, N., Cherniack, A. D., et al. (2013). Integrated
genomic characterization of endometrial carcinoma.
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