Resident Short Review
Undifferentiated Endometrial Carcinoma
A Diagnosis Frequently Overlooked
Shaymaa Al-Loh, MD; Maysa Al-Hussaini, MD, FRCPath
 Undifferentiated endometrial carcinoma (UEC) is a
relatively uncommon neoplasm with only few studies
published thus far. It has always been a diagnostic
challenge because of the lack of proper definition cited
in most of the standard textbooks. Recently however, a few
studies have highlighted the clinicopathologic features of
UEC. The distinctive morphology of UEC was noted by the
group from MD Anderson Cancer Center, which enabled
U ndifferentiated endometrial carcinoma (UEC) has been
concisely referred to only in the most traditional
anatomic pathology textbooks.1 The World Health Organi-
zation (WHO) classification in Tumours of the Breast and
Female Genital Organs2 mentions UEC with only few lines
appended, defining it as carcinoma lacking any evidence of
differentiation. Recently, a few studies3–5 have been
published in the literature, describing histologic findings
of UEC. Its prevalence is believed to be higher than had
been previously thought, as many cases of UEC were either
reported as endometrioid adenocarcinoma FIGO (Interna-
tional Federation of Gynecology and Obstetrics) grade 3,6–8
or as high-grade sarcomas and carcinosarcomas. Undiffer-
entiated endometrial carcinoma, as compared to endome-
trioid adenocarcinoma FIGO grade 3, carries a much worse
prognosis, and presents in a more advanced stage.
Moreover, it has been suggested that UEC may be linked
to the group of tumors belonging to hereditary nonpolyp-
osis colorectal carcinoma or Lynch syndrome, since a
significant percentage of cases display loss of 1 or more of
the DNA mismatch repair genes.5
CLINICAL PRESENTATION
Always thought of as a rare tumor; UEC has accounted for
up to 9% of endometrial carcinomas in some reports.3,9 The
median age at presentation ranges between 50 and 59 years
Accepted for publication May 1, 2012.
From the Department of Pathology and Laboratory Medicine, King
Hussein Cancer Center, Amman, Jordan.
The authors have no relevant financial interest in the products or
companies described in this article.
Presented in part at the 4th International Congress of the Jordanian
Society of Pathology and Laboratory Medicine; April 15, 2011;
Amman, Jordan.
Reprints: Maysa Al-Hussaini, MD, FRCPath, Department of
Pathology and Laboratory Medicine, King Hussein Cancer Center,
Queen Rania St, PO Box 1269, Al-Jubeiha, 11941, Amman, Jordan
(e-mail: mhussaini@khcc.jo).
438 Arch Pathol Lab Med—Vol 137, March 2013
them to establish the defining criteria. It appears to be
more aggressive than endometrial endometrioid adenocar-
cinoma, FIGO (International Federation of Gynecology
and Obstetrics) grade 3, its main differential diagnosis.
Proper recognition of this entity is important owing to its
aggressive behavior.
(Arch Pathol Lab Med. 2013;137:438–442; doi:
10.5858/arpa.2011-0461-RS)
in various studies. However, UEC can affect young-age
groups and accounts for 7% of endometrial carcinomas in
patients younger than 40 years.10 In another study,5 40% of
the patients with UEC were younger than 50 years, with the
youngest reported at 21 years of age. The most common
modes of presentation are postmenopausal bleeding,
vaginal discharge, and abdominal pain. Risk factors reported
in some cases are similar to endometrioid carcinoma and
include hypertension, diabetes, and obesity.3
GROSS PATHOLOGY AND HISTOPATHOLOGY
Undifferentiated endometrial carcinoma may present as
large polypoid masses with evident necrosis. Involvement of
and origin from the lower uterine segment is a frequent
finding, as well as gross involvement of the cervix.5
Microscopically, it is defined as a tumor composed of
medium or large-sized cells with complete absence of
glandular differentiation and with absent or minimal
(,10%) neuroendocrine differentiation.3,4,9 It usually dis-
plays a patternless solid, sheetlike growth, with total
absence of nests, papillae, glands, or trabeculae.3,5 Occa-
sional delicate fibrovascular septae that segregate tumor
cells focally into an alveolar pattern (Figure 1) are described,
as well as vague cords and trabeculae. Large areas of
necrosis with viable perivascular tumor cells are seen. The
cells are dyshesive, mostly monomorphic and relatively
uniform. The nuclei are vesicular with prominent eosino-
philic nucleoli, although they can sometimes be hyperchro-
matic. Variation of cellular size from small cells with scanty
basophilic cytoplasm to large cells with clear or vacuolated
cytoplasm is also described (Figure 2), as well as variable
percentage of tumor cells demonstrating rhabdoid cell
morphology, often in a myxoid background (Figure 3).
Numerous mitoses and also apoptosis are usually seen.
Lymphovascular invasion is seen in more than half of cases.5
Further morphologic characterization was provided by a
comprehensive study with equal contribution by 2 groups,
one from Memorial Sloan-Kettering Cancer Center (New
York, NY) and the other from Stony Brook University
Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini
Medical Center (New York, NY).5 They have concluded that
UEC can present in either pure or mixed forms, a finding
that also applies to similar cases from the ovary. Association
with differentiated components, more commonly of low-
grade (FIGO grade 1 or 2) endometrioid carcinoma, but
occasionally with endometrioid carcinoma FIGO grade 3, is
the defining feature for the mixed forms. Defined as such,
pure forms appear to be more common in some reports,5
while the mixed forms are more common in others.3 In the
mixed forms, which are sometimes referred to as combined
carcinoma5,9 or more appropriately, dedifferentiated carcino-
ma,4,11,12 the percentage of the undifferentiated component
ranged between 20% and 90%,4 and the interface between
the differentiated and the undifferentiated components was
described as abrupt and sharply demarcated, with a more
superficial location for the differentiated component and a
deep location for the undifferentiated carcinoma.5 Occa-
sionally, UEC may be detected asynchronously in the
recurrences or metastasis of an otherwise previously
confirmed and treated endometrial endometrioid adenocar-
cinoma.4 Other specific histologic details displayed by some
UECs were marked nuclear pleomorphism and multi-
nucleation, and prominent tumor-infiltrating lymphocytes.
As originally described, this entity should not show
squamous differentiation, mucinous differentiation, or
spindled growth pattern.3 Later reports, however, allowed
for foci of vague spindling, and abrupt keratinization.4,5

ANCILLARY STUDIES
Immunohistochemical characteristics of UEC include focal
staining (,10%) for keratin AE1/AE35,7, CAM 5.2, and
epithelial membrane antigen (EMA). Others3 have reported
focal (5%–10%) keratin staining (Figure 4) and focal (10%–
20%) EMA staining in most cases. Special emphasis was
given to cytokeratin 18 as being the most helpful stain to
show epithelial differentiation,5 even if more than 1 tumor
block needed to be stained to pick up the very focal
diagnostic staining areas. Of note is the marked intensity of
tumor cells staining for keratins and EMA, regardless of the
percentage of positive cells.3 In addition, UEC showed
reactivity for vimentin (Figure 5) and retained nuclear
staining for BAF-47 (INI-1). One or more neuroendocrine
markers including chromogranin, synaptophysin, and/or
CD56 can be expressed focally in less than 10% to 20% of
tumor cells.4,5 Focal staining for S100 protein, CD10,
estrogen receptor, and progesterone receptor was also
noticed.3,5,7 Completely negative staining for smooth muscle
actin, desmin, and HMB-45 was reported.

PATHOGENESIS
Relation to Lynch syndrome has been suggested after
testing of UEC for DNA mismatch repair (MMR) genes.5,13
Loss of 1 or more of these genes has been reported in 47%
of the tested cases, most frequently, MLH1 and PMS2. The Figure 1. Delicate fibrovascular septae separating groups of tumor
loss was demonstrated in both differentiated and undiffer- cells into alveolar pattern. Note the marked dyshesion of tumor cells
and the scattered mitotic figures (hematoxylin-eosin, original magnifi-
entiated components in tested combined cases, supporting cation 340).
the common origin of both components and thus the
Figure 2. Tumor cells show clear and vacuolated cytoplasm (hema-
designation as dedifferentiated carcinoma. These results toxylin-eosin, original magnification 340).
conferred the property of microsatellite instability to UEC,
Figure 3. Tumor cells with prominent dyshesion and rhabdoid
linking it to hereditary nonpolyposis colorectal carcinoma or
morphology in myxoid background (hematoxylin-eosin, original mag-
Lynch syndrome. MLH1 promoter hypermethylation has nification 340).
been described in a subset of what appeared to be sporadic
cases. The young age of presentation, presence of previous
history of colorectal carcinoma, positive family history for
Arch Pathol Lab Med—Vol 137, March 2013 Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini 439
Figure 4. Cytokeratin MNF immunostain showing focal intense reactivity (original magnification 320).
Figure 5. The tumor is focally positive for vimentin immunostain (original magnification 340).
Figure 6. Cohesive growth of the solid component of the poorly differentiated endometrioid adenocarcinoma, FIGO (International Federation of
Gynecology and Obstetrics) grade 3 (hematoxylin-eosin, original magnification 320).
Figure 7. Cytokeratin MNF immunostain showing diffuse and strong reactivity in poorly differentiated endometrial adenocarcinoma, FIGO
(International Federation of Gynecology and Obstetrics) grade 3 (original magnification 320).

Lynch syndrome–associated tumors, localization to lower
uterine segment, presence of tumor-infiltrating lympho-
cytes, and synchronous ovarian carcinomas10,14 should all
mandate testing of UEC for DNA MMR genes.
DIFFERENTIAL DIAGNOSIS
UEC Versus Endometrioid Adenocarcinoma FIGO Grade 3
Undifferentiated endometrial carcinoma is most frequent-
ly misdiagnosed as endometrial endometrioid adenocarci-
noma, FIGO grade 3. However, the latter is defined by the
WHO as composed of 1% to 49% glandular areas. Although
the presence of focal glandular differentiation can help in
separating endometrial endometrioid adenocarcinoma,
FIGO grade 3, from pure forms of UEC, this feature loses
its power in cases of mixed forms of UEC or dedifferentiated
carcinoma, where the UEC component is mostly seen
admixed with lower-grade endometrioid carcinoma. The
presence of cohesive sheets of neoplastic cells in solid areas
440 Arch Pathol Lab Med—Vol 137, March 2013
(Figure 6), the comparable cytologic features in the
glandular and solid components, the absence of rhabdoid
features, and the diffuse immunoreactivity for keratins
(Figure 7) and EMA can help to support the diagnosis of
poorly differentiated endometrioid adenocarcinoma.3 The
cytologic features of UEC and differentiated components in
the dedifferentiated carcinoma are distinct.5 The Table
summarizes the main differences between UEC and
endometrioid adenocarcinoma FIGO grade 3.
UEC Versus Neuroendocrine Carcinoma
Neuroendocrine carcinoma is another important differ-
ential diagnosis. Tumors that usually had been referred to in
the literature as small and large cell carcinomas should be
regarded as neuroendocrine carcinomas rather than variants
of UEC, as they do display a form of differentiation, which
goes against the definition of undifferentiated carcinoma.
Expression of 1 or more neuroendocrine markers, including
Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini
 Clinicopathologic Features of Undifferentiated Endometrial Carcinoma/Dedifferentiated Carcinoma
and Endometrial Endometrioid Adenocarcinoma, FIGO Grade 3
Undifferentiated/Dedifferentiated Endometrial Adenocarcinoma,
Endometrial Carcinoma FIGO Grade 3
Clinical features3
Mean age at presentation, y 55 68
High stage (stage III/IV), % 45 30
Morphology
Growth pattern Diffuse patternless sheetsa Solid and glandular
Glands Absenta Present (1%–49% of tumor area)
Cords and trabeculae Vaguea Well demarcated
Cohesive growth Dyshesive cells Cohesive squamoidlike
Component demarcation Sharp demarcation Intermingled components
Rhabdoid cells May be present Absent
Myxoid matrix May be present Absent
Immunohistochemistry
Pancytokeratin Patchy/focal Diffuseb
EMA Patchy/focal Diffuseb
ER/PR Focal in 12% of cases Diffuseb in 60% of cases

Abbreviations: EMA, epithelial membrane antigen; ER, estrogen receptor; FIGO, International Federation of Gynecology and Obstetrics; PR,
progesterone receptor.
a
This applies only to pure forms of undifferentiated endometrial carcinoma, as glandular component can be seen in the lower-grade component of
the dedifferentiated carcinoma.
b
Diffuse staining is defined as staining in more than 50% of tumor cells.

synaptophysin, chromogranin, and/or CD56 in more than
20% of tumor cells, should support this diagnosis.5,9
UEC Versus Serous Carcinoma
Serous carcinoma with solid growth pattern tends to
show distinctive high-grade cytologic findings, in addition
to the papillary and/or slitlike spaces. Frequent lymphovas-
cular invasion with papillary formations is seen frequently in
the advancing edge of the tumor. In addition; psammoma
bodies are indentified in one-third of cases of serous
carcinoma.15
UEC Versus Carcinosarcoma
Carcinosarcoma affects elderly females and would evi-
dently display a biphasic pattern, associated usually with
high-grade carcinomatous component, most frequently
serous carcinoma, and a pleomorphic, typically spindle-cell
sarcomatous component.
UEC Versus Sarcoma
Endometrial stromal tumors, especially undifferentiated
endometrial sarcoma (UES), should be considered in the
differential diagnosis. This is a high-grade tumor with
marked pleomorphism, brisk mitosis, and necrosis. Al-
though UES might show some staining with CD10, it is
nonreactive for other markers, including epithelial markers,5
and extensive sampling to rule out the presence of focal
areas of differentiation should always be performed. High-
grade endometrial stromal sarcoma is a recently ‘‘revisited’’
entity, with intermediate features between low-grade
endometrial stromal sarcoma and UES. It exhibits uniform
cells with evidence of endometrial stromal differentiation.16
Epithelioid leiomyosarcoma is ruled out through negativ-
ity for muscle markers including desmin, smooth muscle
actin, and h-caldesmon. Pancytokeratin staining should be
cautiously interpreted in epithelioid leiomyosarcoma as it
can show positivity.17
Others
The striking dyshesion of the UEC tumor cells makes
lymphoma, plasmacytoma, and granulocytic sarcoma enter
Arch Pathol Lab Med—Vol 137, March 2013
the list of the differential diagnoses. Nonetheless, immu-
nophenotyping makes the distinction quite easy.
CURRENT TREATMENT AND PROGNOSIS
Undifferentiated endometrial carcinoma appears to pur-
sue an aggressive clinical course with advanced stage at
presentation and a median survival of 6 months. Disease-
related death rate ranges from 41% to 75% of reported
cases, which occurs mostly in the first 5 years after
diagnosis. According to Altrabulsi et al,3 54% of UECs
present as high-stage disease (stage III or IV), as compared
to 30% of endometrioid adenocarcinomas FIGO grade 3.
Pelvic and paraaortic lymph nodes are the most common
sites of metastasis. Silva et al4 and Tafe et al5 noted that in
cases of combined histologic appearance, the presence of
even a small undifferentiated component appears to carry a
poor clinical outcome, while the presence of a better-
differentiated component, irrespective of its extent, does not
appear to confer improved clinical outcome. No association
was found between age, stage, presence and number of
tumor-infiltrating lymphocytes, rhabdoid cell morphology,
and clinical outcome.5
Treatment modalities include total abdominal hysterecto-
my and bilateral salpingo-oopherectomy, as well as
chemotherapy and radiotherapy, with regimens similar to
those for endometrioid carcinoma FIGO grade 3. Hayashi et
al18 reported a successful experience with a case of UEC that
was treated by surgery in conjunction with a combination
chemotherapy regimen consisting of tetrahydropryanyl-
adriamycin, taxane (paclitaxel), and JM-8 (carboplatin), the
TTJ regimen. The patient was treated with 6 cycles of TTJ
and achieved complete response. She continued to be
carefully followed up by clinical examination, magnetic
resonance imaging, and bone scan. She was followed up for
41 months and remained alive without metastasis. Another
example of long survival is that of a patient with advanced-
stage disease who was treated exclusively with radiotherapy
and showed no evidence of disease after a follow-up of 104
months.3
Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini 441
 POINTS OF CONTROVERSIES
Are UEC and Neuroendocrine Carcinoma
the Same or Different?
The exact relation between neuroendocrine carcinoma and
UEC needs further elaboration. Focal neuroendocrine differ-
entiation, defined as less than 10% positivity of various
intensities with 1 or more neuroendocrine markers, was
reported in 41% of UECs by Taraif et al.19 Interestingly, there
was no difference in the prognosis and overall survival
between both groups.19 Within UEC, this focal neuroendocrine
differentiation does not seem to affect the outcome either.4
What Is the Difference Between Pure Forms of UEC
and Mixed or Dedifferentiated Carcinoma Forms?
Microsatellite instability immunostaining performed in
some cases is in support of a common origin of the better
differentiated and undifferentiated components in the mixed
tumors; thus, the suggested term dedifferentiated carcino-
ma.4,5 Treatment protocols are similar in both scenarios, as
pure and mixed forms of UEC are treated as endometrioid
carcinoma FIGO grade 3. Prognosis is reported to be poor
regardless of the amount of undifferentiated component,
and the presence of a better-differentiated component,
irrespective of its extent, does not appear to confer an
improved clinical outcome. Total engulfment of the better-
differentiated component by the undifferentiated one might
offer a reasonable possible explanation.
The authors thank Dean Daya, MD, MHA, FRCPC, at
Henderson General Hospital, Hamilton, Ontario, Canada, for the
constructive review of the manuscript.
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442 Arch Pathol Lab Med—Vol 137, March 2013 Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini