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

them to establish the defining criteria. It appears to be

more aggressive than endometrial endometrioid adenocarcinoma, 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;137:438442; 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

ndifferentiated endometrial carcinoma (UEC) has been

concisely referred to only in the most traditional
anatomic pathology textbooks.1 The World Health Organization (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 studies35 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 (International Federation of Gynecology and Obstetrics) grade 3,68
or as high-grade sarcomas and carcinosarcomas. Undifferentiated endometrial carcinoma, as compared to endometrioid 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 nonpolyposis 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 MedVol 137, March 2013

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 displays a patternless solid, sheetlike growth, with total
absence of nests, papillae, glands, or trabeculae.3,5 Occasional 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 eosinophilic nucleoli, although they can sometimes be hyperchromatic. 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 CarcinomaAl-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 lowgrade (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 carcinoma,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 Occasionally, UEC may be detected asynchronously in the
recurrences or metastasis of an otherwise previously
confirmed and treated endometrial endometrioid adenocarcinoma.4 Other specific histologic details displayed by some
UECs were marked nuclear pleomorphism and multinucleation, 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
loss was demonstrated in both differentiated and undifferentiated components in tested combined cases, supporting
the common origin of both components and thus the
designation as dedifferentiated carcinoma. These results
conferred the property of microsatellite instability to UEC,
linking it to hereditary nonpolyposis colorectal carcinoma or
Lynch syndrome. MLH1 promoter hypermethylation has
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 MedVol 137, March 2013

Figure 1. Delicate fibrovascular septae separating groups of tumor

cells into alveolar pattern. Note the marked dyshesion of tumor cells
and the scattered mitotic figures (hematoxylin-eosin, original magnification 340).
Figure 2. Tumor cells show clear and vacuolated cytoplasm (hematoxylin-eosin, original magnification 340).
Figure 3. Tumor cells with prominent dyshesion and rhabdoid
morphology in myxoid background (hematoxylin-eosin, original magnification 340).

Undifferentiated Endometrial CarcinomaAl-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 syndromeassociated tumors, localization to lower

uterine segment, presence of tumor-infiltrating lymphocytes, 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 frequently misdiagnosed as endometrial endometrioid adenocarcinoma, 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 MedVol 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 differential 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 CarcinomaAl-Loh & Al-Hussaini

Clinicopathologic Features of Undifferentiated Endometrial Carcinoma/Dedifferentiated Carcinoma

and Endometrial Endometrioid Adenocarcinoma, FIGO Grade 3

Clinical features3
Mean age at presentation, y
High stage (stage III/IV), %
Morphology
Growth pattern
Glands
Cords and trabeculae
Cohesive growth
Component demarcation
Rhabdoid cells
Myxoid matrix
Immunohistochemistry
Pancytokeratin
EMA
ER/PR

Undifferentiated/Dedifferentiated
Endometrial Carcinoma

Endometrial Adenocarcinoma,
FIGO Grade 3

55
45

68
30

Diffuse patternless sheetsa

Absenta
Vaguea
Dyshesive cells
Sharp demarcation
May be present
May be present

Solid and glandular

Present (1%49% of tumor area)
Well demarcated
Cohesive squamoidlike
Intermingled components
Absent
Absent

Patchy/focal
Patchy/focal
Focal in 12% of cases

Diffuseb
Diffuseb
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

the list of the differential diagnoses. Nonetheless, immunophenotyping makes the distinction quite easy.

UEC Versus Serous Carcinoma

CURRENT TREATMENT AND PROGNOSIS

Serous carcinoma with solid growth pattern tends to

show distinctive high-grade cytologic findings, in addition
to the papillary and/or slitlike spaces. Frequent lymphovascular 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

Undifferentiated endometrial carcinoma appears to pursue an aggressive clinical course with advanced stage at
presentation and a median survival of 6 months. Diseaserelated 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 betterdifferentiated 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 hysterectomy 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 tetrahydropryanyladriamycin, 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 advancedstage disease who was treated exclusively with radiotherapy
and showed no evidence of disease after a follow-up of 104
months.3

UEC Versus Carcinosarcoma

Carcinosarcoma affects elderly females and would evidently 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. Although 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. Highgrade 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 negativity 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
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Undifferentiated Endometrial CarcinomaAl-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 differentiation, 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 carcinoma.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 betterdifferentiated 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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CAP 13 Abstract Program Accepting Submissions

Abstract and case study submissions will be accepted beginning Monday, February 4,
2013 for the College of American Pathologists (CAP) 2013 meeting. CAP 13 will be held
October 13 through the 16th in Orlando, Florida. Submissions for the CAP 13 Abstract
Program will be accepted through Monday, April 1, 2013.
Accepted submissions will appear in the October 2013 issue of the Archives of Pathology
& Laboratory Medicine. Visit the CAP 13 Website at www.cap.org/cap13 for a link to the
abstract submission site and additional abstract program information as it becomes
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442 Arch Pathol Lab MedVol 137, March 2013

Undifferentiated Endometrial CarcinomaAl-Loh & Al-Hussaini