Review Article

Histopathology of endometrial hyperplasia and endometrial carcinoma

An update
Lars-Christian Horn, MD, PhD
a,

, Alexandra Meinel, MSc

a
,
Romy Handzel, MSc
b
, Jens Einenkel, MD
b
a
Division of Gynecologic Pathology, Institute of Pathology, Leipzig University, D-04103 Leipzig, Germany
b
Department of Obstetrics and Gynecology, Leipzig University, D-04103 Leipzig, Germany
Abstract Endometrial cancer (EC) is the most common malignancy of the female genital tract in the western
world. Conceptually, a dualistic model of endometrial carcinogenesis exists for sporadic EC, based
on molecular findings with a good correlation to the morphologic phenotype and clinical behavior.
Type 1 endometrial carcinoma represents an estrogen-related tumor, which usually arises in the
setting of endometrial hyperplasia, has endometrioid histology with low grade, and tends to be
biologically indolent. Grade 3 endometrioid cancers, which constitute a minority of EC, also behave
aggressively. The type 2 cancers are not estrogen-driven and have a higher grade, various histologies,
particularly serous carcinomas and clear-cell carcinomas, and a poorer prognosis. The diagnostic
criteria of endometrial hyperplasia, endometrial in situ carcinoma, and of the different histologic
types of EC, according to the most recent World Health Organization classification, are given in
detail. In addition, the risk of progression of endometrial hyperplasia into endometrioid type EC and
their treatment modalities are discussed. Endometrial pathologies in patients with breast cancer,
receiving tamoxifen, and women affected by hereditary nonpolyposis colorectal cancer syndrome are
described, including their pathogenetic aspects. Finally, a short practical description for the handling
of surgical specimens from fractional curetting and hysterctomies is given.
2007 Elsevier Inc. All rights reserved.
Keywords: Endometrial carcinoma; Endometrial hyperplasia; Type 1 and type 2 carcinoma; Microscopy; Surgical pathology
1. Introduction
During the last decades, a change of demographics has
occurred. The number of women more than 60 years of age is
increasing worldwide, with increasing life span. In addition,
women in the 21st century will also experience menarche at a
younger age than earlier generations, will typically (espe-
cially in countries of the western world) have fewer children,
and, as a consequence, spend less time breast-feeding. In
addition, they will enter the menopause stage later as some
decades before. As one consequence, the focus for the aging
woman will be on lifestyle support to counteract various
features of degenerative changes. This will be accompanied
by an increasing demand for medical expertise on lifestyle
drugs, for example, the use of hormone replacement therapy.
In addition, there is an increase in malignant diseases
worldwide, also in women [1]. All these factors might also
associate with a potential increase in endometrial malig-
nancies and their precursors. Endometrial cancer (EC) is the
most common invasive malignancy of the female genital tract
with an estimated incidence of 39.080 new cases in the
United States of America for 2007 [2]. In Germany, there are
about 11,300 estimated cases each year [3], representing the
fourth most common cancer in women and the number one in
cancers of the female genital tract.
Historically, more than 23 years ago, Bokhman [4]
classified endometrial carcinomas into 2 types. Although
this classification is an oversimplification, it is of
use conceptually. The so-called type 1 endometrial carcinoma
represents an estrogen-related carcinoma, usually arises in the
setting of endometrial hyperplasia and have endometrioid
Annals of Diagnostic Pathology 11 (2007) 297311

Corresponding author. Tel.: +49 341 97 150 46; fax: +49 341 97 23 549.
E-mail address: hornl@medizin.uni-leipzig.de (L.-C. Horn).
1092-9134/$ see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.anndiagpath.2007.05.002
histology with low grade, and tends to be biologically
indolent. However, grade 3 endometrioid cancers, which
constitute a minority of EC, also behave aggressively.
The type 2 cancers are not estrogen-driven and have a
higher grade, various histologies, particularly serous carci-
nomas and clear-cell carcinomas, and a poorer prognosis.
Table 1 lists the classic features of the 2 categories [5,6].
Black women have substantially more aggressive tumor
types than do white non-Hispanic women, including serous
carcinoma and clear-cell carcinoma, and have a worse overall
survival for all tumor types [7].
Based on these features, a dualistic model of endometrial
carcinogenesis for sporadic EC has been proposed [8,9].
The present review will summarize the morphologic
features of the different types of endometrial carcinomas,
their precursors, and of rare ECs in recognition experiences
and recent published updates [10-16]. In addition, a short
update on handling and histopathologic reporting of curet-
tings and hysterectomy specimens in endometrial hyperplasia
and carcinoma will be given at the end of this article.
Malignant mixed mullerian tumors are not included in
this article and have been reviewed recently [15].
2. Endometrial hyperplasia
Endometrial hyperplasia represents a nonphysiological,
noninvasive proliferation of the endometrium that results in a
morphologic pattern of glands with irregular shapes and
varying size [9,12]. There are 2 forms of hyperplasia, one
(atypical) that is closely related to adenocarcinoma, being an
apparent precursor lesion, and another (nonatypical) that is
largely self-limited with little apparent relationship to
carcinoma [17-19]. The World Health Organization (WHO)
classification of endometrial hyperplasia is summarized in
Table 2. Correct identification and classification of hyper-
plasia are especially important in endometrial biopsy and
curettage specimens because proper diagnosis guides clinical
therapy [20], which can be very different depending on the
type of hyperplasia found.
3. Histopathology of endometrial hyperplasia associated
with type 1 carcinoma
All forms of hyperplasia share certain morphologic
features, showing an increase in the gland-stroma ratio,
irregularities in gland shape, and variation in gland size
[13,14]. The leading clinical symptom is irregular bleeding.
The amount of tissue obtained at curettage may be
considerable, sometimes yielding enough to fill 3 or more
tissue cassettes.
Simple and complex forms of hyperplasia are distin-
guished by architectural alterations characterized by
Table 1
Principal types of endometrial carcinoma
Type I Type II
Menopausal status Premenopausal and
perimenopausal
Postmenopausal
Estrogen-related Yes No
Estrogen or
progesterone
receptors
Present Absent
Histology of
adjacent
endometrium
Hyperplastic Atrophic/cystic polyp
Precursor lesion Atypical hyperplasia EIC
Obesity Yes No
Parity Nulliparous Multiparous
Grade Low High
Histologic subtype Endometrioid Serous carcinoma
clear-cell carcinoma
Clinical behavior Indolent Aggressive
Table 2
World Health Organization classification of endometrial hyperplasia
(Silverberg et al [14])
Nonatypical hyperplasias (typical)
Simple hyperplasia without atypia
Complex hyperplasia without atypia (syn. adenomatous hyperplasia
without atypia)
Atypical hyperplasias
Simple atypical hyperplasia
Complex atypical hyperplasia (syn. atypical adenomatous hyperplasia)
Fig. 1. Simple hyperplasia without atypia: proliferated endometrial glands
with irregular distribution and cystic dilatation, but widely separated by
endometrial stroma, which is also hyperplastic (A). Glands are lined by
proliferative-type endometrial epithelium without atypia (B).
298 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
glandular complexity and the amount of stroma separating
the glands, regardless of the presence of atypia. Hyperplasia
is generally a diffuse abnormality, involving much often the
whole endometrium, often with polypoid growth. However,
sometimes, hyperplasia may be present as a localized lesion
and might be associated within an endometrial polyp. Most
endometrial hyperplasias are estrogen-driven and related to
the type 1 endometrial carcinoma, the endometrioid
endometrial adenocarcinoma.
Simple hyperplasia, previously referred to as cystic
hyperplasia, features proliferating glands with irregular
size with cystic appearance and shape, yet separated by
abundant stroma (Fig. 1). The glandular architectural changes
are characterized by varying degrees of irregular branching
with infoldings and outpouchings. Cytologically, the glandu-
lar epithelium resembles proliferative endometrium. The
cells of the columnar epithelium maintain their orientation
to the underlying basement membrane.
The complex hyperplasia, previously termed adenoma-
tous hyperplasia, shows more densely crowded glands
(Fig. 2). In addition, the glands may demonstrate increased
structural complexity with more outpouchings and infold-
ings. Usually, the glands are closely packed and represent a
back-to-back position, although intervening stroma is
consistently present. There should be at least twice as many
glands as stroma in any field for a gland-stroma ratio of more
than 2:1 [13]. However, cystic glands can involve a portion
of the endometrium in complex hyperplasia, and mixtures of
simple and complex hyperplasia may be seen. For practical
reasons, the histopathologic report should point out the
complex form as the more relevant lesion (see below and
Table 3). Cytologically, the cells of complex hyperplasia are
closely related to simple hyperplasia.
The WHO classification includes a lesion termed simple
atypical hyperplasia [14]. However, in contrast to non-
atypical hyperplasia, most cases of atypical hyperplasia have
a complex pattern with closely apposed glands (complex
atypical hyperplasia) [17]. In a large retrospective analysis,
no case of simple atypical hyperplasia has been found in our
retrospective screened material [17]. In accordance with
others, we assume that this category, if it does exist, is
extremely rare [21,22].
In case of complex atypical hyperplasia, the glands tend to
be highly irregular in size and shape, sometimes associated
with papillary infolding into the lumen of the proliferated
glands. The glands in atypical hyperplasia are very closely
packed with a prominent back-to-back position. The
endometrial stroma might be seen, separating the glands,
and each gland represents a basement membrane separating it
from adjacent glands [14]. The diagnosis of atypia is based
mainly on specific nuclear features and usually is accom-
panied by true stratification [13] (Fig. 3): Many of the nuclei
are enlarged and rounded rather than oval and may have
irregular nuclear membranes with a loss of polarity in relation
to the basement membrane. The nuclear chromatin is
irregular and sometimes dispersed along the nuclear
membrane, resulting in a distinctive vesicular appearance
that is highly characteristic of endometrial atypia. The
nucleoli might be prominent.
The risk of progression of endometrial hyperplasia into
endometrioid carcinoma is more closely related to the
presence of cytologic atypia and to architectural crowding.
There are some studies dealing with the risk of progression
of the different types of endometrial hyperplasia into
endometrioid type of endometrial adenocarcinoma (type 1
carcinoma). Their results are summarized in Table 3.
It is noteworthy to point out that in patients who
undergo a hysterectomy soon after the biopsy/curettage
Fig. 2. Complex hyperplasia without atypia: closely packed endometrial
glands with irregular distribution, separated by abundant endometrial stroma
(A). Glands are lined by proliferative-type endometrial epithelium without
atypia (B).
Table 3
Risk of EC in different types of endometrial hyperplasia
Simple
hyperplasia
Complex
hyperplasia
Atypical
hyperplasia
Kurman
et al,
1985
1/93 (1.1%) 1/29 (3.4%) 10/35 (28.6%)
Baak et al,
1992
0/8 (0%) 1/6 (16.7%) 5/11 (45.4%)
Horn et al,
2004
8/390 (2.0%) 58/112 (51.8%)
Overall risk 1/101 (1.0%) 15/425 (3.5%) 73/158 (46.2%)
299 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
diagnosis of atypical hyperplasia, the hyperplasia was
associated with an endometrioid carcinoma in 17% to
43% of the cases [23-27]. Mecke et al [27] reported 3
cancers in 56 resected uteri for complex hyperplasia
(5.3%) within 4 weeks. Eight cancers were detected after
an initial diagnosis of atypical hyperplasia (57.1%) [27].
In a large study of 560 endometrial hyperplasias, 6.4%
patients represented type 1 endometrial carcinoma at
hysterectomy [17]. These data support the fact that the
atypical complex hyperplasia is a direct precancerous
lesion of the endometrioid adenocarcinoma. When adeno-
carcinoma is present after a biopsy diagnosis of atypical
hyperplasia, the neoplasm is almost always well differ-
entiated, focal, and either confined to the endometrium or
minimally invasive into the myometrium [17,27].
The atypical complex hyperplasia harbors a broad
spectrum of differential diagnoses. At one end, the cytologic
changes of atypia must be distinguished from benign
abnormalities such as cytoplasmic change (metaplasia).
These metaplastic changes include eosinophilic change,
squamous cell, ciliated cell, and mucinous metaplasia.
Their histopathology should not be discussed here; a
comprehensive review is recently published [13]. At the
other end of the spectrum, well-differentiated endometrioid
adenocarcinoma have to be differentiated. The features for
differential diagnosis will be briefly discussed in the chapter
about type 1 endometrial carcinoma (see below).
There is a discussion to replace the current WHO
classification of the precursors of type 1 endometrial
carcinoma (see Table 2) by the term endometrial hyperplasia
(without specification) and the term endometrial intraepithe-
lial neoplasia (EIN) [28]. By definition, the EIN represents
the histopathologic presentation of a monoclonal endometrial
preinvasive glandular proliferation that is the immediate
precursor of the endometrial type 1 adenocarcinoma.
Histopathologically, the EIN is characterized by a prolifera-
tion of endometrial glands that exceeds the stroma (gland/
stroma N1) with a maximum linear dimension exceeding 1
mm. Cytologically, the nuclear and/or cytoplasmic features of
the glands of EIN differ between the glands with abnormal
architecture and those with the normal background of the
individual case [28]. However, this classification is currently
under discussion and should not replace the recent WHO
classification of endometrial hyperplasia.
Therapeutically, the atypical hyperplasia in peri- and
postmenopausal women should be treated with simple
total hysterectomy. In older women with multimorbidity
Fig. 3. Atypical hyperplasia: very closely packed irregular-shaped
endometrial gland separated by hyperplastic endometrial stroma (A). Glands
are lined by hyperchromatic epithelium with nuclear atypia (B).
Fig. 4. Treatment modalities of endometrial hyperplasia of the German Working Group of Gynecologic Oncology (see text). mp indicates menopausal.
300 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
and reduced operability as well as in premenopausal
women, the atypical hyperplasia can be treated with
progestogens [29,30]. In cases of atypical hyperplasia,
Randall and Kurman [29] reported regression in 16 of 17
patients treated with progestagens. In endometroid cancer,
a cure rate of about 66% has been reported [29,30]. The
success of hormonal treatment in those cases probably
could be improved by a combination of progestogens and
gonadotropin releasing hormone (GnRH) analogues
[30,31]. xThis therapeuticalx decision may be indirectly
supported by the fact that endometrial carcinoma asso-
ciated with hyperplasia have a better prognosis than
cancers without hyperplasia on resected uteri [32].
The correct diagnosis of endometrial hyperplasia is very
important because proper diagnosis guides clinical therapy.
The different types of treatment modalities of the German
Working Group of Gynecologic Oncology (AGO) to manage
endometrial hyperplasia are summarized in Fig. 4.
4. Histopathology of precursor lesions associated with
type 2 carcinoma
Endometrial intraepithelial carcinoma (EIC) is different
from atypical hyperplasia and represents the precursor lesion
of serous carcinoma (the prototype of the type 2 carcinoma)
[14,33,34]. The EIC represents a noninvasive glandular
lesion characterized by epithelial cells with marked nuclear
abnormalities, resembling nuclei similar to those seen in
serous carcinoma of the endometrium.
In most cases, the EIC is not associated with hyperplasia
and does not typically occur in the clinical setting of increased
estrogen exposure but instead is seen in atrophic endome-
trium of older postmenopausal women, and not rarely, it
occurs within a polyp [35]. The lesion involves surface
epithelium and may extend into atrophic glands. In our
opinion, it is the question at times, whether the above-
mentioned cases of simple atypical hyperplasia represent
cases of EIC where the alterations of the surface epithelium
are not apparent in the examined material. The cells of EIC
are polygonal and hobnail with highly irregular nuclei. The
cells of EIC typically are reactive to p53 [36] and show a
diffuse intense reactivity to Ki-67, reflecting their high
proliferative rate, but are typically negative against estrogen
and progesterone receptor analysis (Fig. 5). The term EIC
should be used for all lesions meeting the above-mentioned
criteria, and the term endometrial glandular dysplasia [37]
should be avoided because these lesions represent identical
morphologic and immunohistochemical features of EIC.
Therapeutically, the EIC will be handled as type 2 carcinoma
at times ([36]; see below).
5. Histopathology of endometrial adenocarcinomas
The current WHO classification gives different histologic
types of endometrial carcinoma (Table 4).
As mentioned earlier, based on clinical and pathologic
features, Bokhman [4] classified endometrial carcinomas
into 2 types (see above and Table 1). Based on these features
and recent molecular data, a so-called dualistic model of
endometrial carcinogenesis for sporadic EC has been
proposed [5,8,9]. In this model, there are 2 main types of
endometrial carcinomas: a slowly developing, indolent form
that develops in the setting of excess estrogen stimulation
and association with endometrial hyperplasia (type 1
carcinoma) and a more aggressive variant arising in a
relatively estrogen-deficient milieu, which represents an
association with EIC (type 2 carcinomas). The different
histologic features of endometrial carcinomas of this
dualistic model and of other histologic types will be
described briefly.
Fig. 5. Endometrial in situ carcinoma (EIC): endometrial surface
epithelium represents a small papillary proliferation of small-sized cells
with very hyperchromatic nuclei without infiltration of endometrial
stroma (A). These cells are negative for estrogeneous receptor analysis
(B) but positive for p53 (C).
301 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
6. Histopathology of endometrioid adenocarcinoma of
the endometrium (type 1 carcinomas)
The prototype of the type 1 endometrial adenocarcinoma
of the endometrium is the endometrioid carcinoma (Fig. 6).
This diagnosis is established readily when there is myome-
trial invasion, but this is a rare finding in curettings [13].
Thus, on curettings, the diagnosis of well-differentiated
endometrial adenocarcinoma is based on identifying invasion
of endometrial stroma. There are 3 essential criteria, any of
which identifies endometrial stromal invasion [13,23,38,39]:
a confluent glandular pattern in which individual
glands, uninterrupted by stroma, merge and create a
cribriform pattern;
an extensive papillary pattern; and
an irregular infiltration of glands associated with an
altered fibroblastic stroma (desmoplastic stromal
response).
Using these straightforward criteria, cases are identified,
which often have significant carcinoma in hysterectomy
specimens [17,27,38], and most represents FIGO grade 1
lesions [17], but FIGO grade 2 or 3 may also occur. The
definition of different grades is summarized in Table 5.
As in endometrial hyperplasia, metaplastic change may
occur in basically endometrioid adenocarcinomas and may
provoke differential diagnostic problems [40]. These meta-
plastic changes do not alter the denomination of these
neoplasms as type 1 carcinomas because of the proposed
pathogenetic model (Fig. 7).
Especially, the villoglandular type of endometrioid
adenocarcinoma (Fig. 8) should not be confused with serous
carcinoma. In doubtful cases, immunohistochemistry might
be helpful. Contrary to serous endometrial carcinoma, the
villoglandular type is strongly positive for estrogen and
progesterone receptor, but negative for p53 in most FIGO
grade 1 and cases with low Ki-67 labeling index.
In 1988, Mittal and Barwick [41] reported an unusual type
of endometrioid adenocarcinoma with deep infiltration of the
myometrium and poor prognostic outcome, but well
differentiated endometrioid histology [42]. Further studies
referred this type of carcinoma as minimal deviation type of
endometrioid adenocarcinoma (Fig. 9). The frequency of this
special type is of about 3% [41], and focal transitional areas
between typical and minimal deviation endometrioid adeno-
carcinoma can be identified [42,43]. The lesion may occur in
the isthmus of the uterus [44]. On immunohistochemistry, the
minimal deviation endometrioid adenocarcinoma has been
reported to be positive for estrogen and progesterone receptor
analysis, CK7 and vimentin, but negative for CK20 and p53
in the evaluated cases [42]. Minimal deviation adenocarci-
noma of endometrioid type more often develops as a result of
differentiation from typical endometrioid adenocarcinoma
than de novo. Because of its deceptively benign microscopic
appearance, minimal deviation adenocarcinoma of endome-
trioid type may be overlooked and may lead to incorrect
assessment of tumor depth and pathological stage. Although
the prognosis of minimal deviation type of endometrioid
adenocarcinoma might be the same as in well-differentiated
conventional endometrioid adenocarcinoma [45], this sub-
type should be given in the pathology report.
7. Histopathology of type 2 carcinomas
The prototype of the type 2 endometrial adenocarcinoma
of the endometrium is the serous and the clear-cell carci-
noma. Their histogenetic concept is illustrated in Fig. 10.
In 1982, Hendrickson et al [46] described uterine serous
carcinoma as a highly malignant subtype of endometrial
carcinoma. Patients with serous carcinoma are at median of
5 years older than those with endometrioid cancers [16]. Like
endometrioid cancer, it usually presents with vaginal
bleeding. Serous carcinoma accounts for less than 10% of
endometrial malignancies [47] with poor prognosis [16,48],
seen most often in postmenopausal women against a
background of atrophic endometrium. The transition
between nonneoplatsic and neoplastic areas might be abrupt.
As mentioned above, serous carcinoma arises from EIC in up
to 90% of cases, but the distinction between EIC and
invasive disease with glandular growth pattern is difficult
[33,49]. Spread of serous carcinoma is commonly intra-
abdominal, in a manner resembling ovarian cancer.
Histologic diagnosis can often be made from dilation and
curettage samples. In the designation of this lesion, the term
papillary should not be used to avoid the misinterpretation of
that highly aggressive tumor with villoglandular variant of
endometrioid adenocarcinomas, which are low-grade ECs.
Serous carcinomas are composed of cuboidal or hobnail-
shaped pleomorphic cells, which are smaller than those of
endometrioid adenocarcinoma and have eosinophilic cyto-
plasm that shows focal clearing. The nuclei are apical-
located and range in size from small vesicular forms to large,
pleomorphic hyperchromatic ones with prominent eosino-
philic nucleoli, frequent mitotic figures, and occasional
Table 4
World Health Organization classification of endometrial hyperplasia
(Silverberg et al [14]) with International Classification of Diseases-Oncology
(ICD-O) codes
Histologic type ICD-O codes
Endometrioid adenocarcinoma 8380/3
Variant with squamous differentiation 8570/3
Villoglandular variant 8262/3
Secretory variant 8382/3
Ciliated cell variant 8383/3
Mucinous adenocarcinoma 8480/3
Serous adenocarcinoma 8441/3
Clear-cell adenocarcinoma 8310/3
Mixed adenocarcinoma 8323/3
Squamous-cell carcinoma 8070/3
Transitional-cell carcinoma 8120/3
Small-cell carcinoma 8041/3
Undifferentiated carcinoma 8020/3
302 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
bizarre forms (Fig. 11) [11]. In contrast to villoglandular type
of endometrioid carcinoma, the papillae have a complex
architecture, with uneven borders and cores that may be
edematous or hyalinized (Fig. 8). Necroses are common, and
psammoma bodies might be present.
Uterine serous carcinomas, unlike uterine endometrioid
carcinomas, tend not to express estrogen and progesterone
receptors but are diffuse positive with p53 and represent a
high Ki-67 labeling index and also Her-2/neu expression
[50,51]. In contrast to serous carcinoma of the ovary and the
peritoneum, uterine serous carcinomas are negative against
WT-1 in most cases [52].
A recent study has compared the prognosis of uterine
serous carcinoma with FIGO grade 3 endometrioid
Fig. 6. Endometrioid adenocarcinoma with stromal invasion: confluent glandular pattern in which individual glands, uninterrupted by stroma, merge and create a
cribriform pattern (A), extensive papillary pattern (B), and infiltration of glands associated with desmoplastic stromal response (C and D).
Table 5
FIGO-grading of type I endometrial adenocarcinoma (endometrioid and mucinous)
- Grade 1: 5% nonsquamous, nonmorular growth pattern
- Grade 2: 6%-50% nonsquamous, nonmorular growth pattern
- Grade 3: N50% nonsquamous, nonmorular growth pattern
Note: squamous/morular components are excluded from grading. Bizarre nuclear atypia should raise the grade by one (ie, from 1 to 2 or 2 to 3) but may also
signify type 2 differentiation.
303 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
adenocarcinoma [53]. This study reported that patients with
serous carcinoma involving N50% of an endometrial
carcinoma represent a much worse prognosis compared
with the overall survival of women with FIGO grade
3 endometrioid carcinoma. In patients with early-stage
disease, a trend toward a worse prognosis was found to
exist when serous carcinoma comprised even 10%of a tumor.
So, in mixed serous and endometrioid carcinomas, the
percentage of serous differentiated should be given in the
pathologic report. The exact histopathologic diagnosis of
uterine serous carcinoma is very important because routine
extended surgical staging is usually recommended, as it is for
ovarian carcinoma, when uterine serous carcinoma pathology
is suspected [48]. Because of a high risk of extrauterine
spread by the time of diagnosis, systemic chemotherapy is
recommended as a part of standardized treatment of this
uterine malignancy [16,20].
Clear-cell carcinoma has epidemiological features similar
to those of serous carcinoma and represents a type 2
carcinoma. It develops more frequently in postmenopausal
patients who are not obese, is not associated with estrogen
application, and is more common in black women and
accounts for about 5% of all ECs.
Clear-cell carcinomas are aggressive and have a tendency
to relapse outside of the pelvis [54,55]. Cirisano et al [56]
showed that up to 40% of patients with clear-cell carcinoma
that was clinically confined to the uterus had extrauterine
spread and that, similar to patients with uterine serous
carcinoma, extrauterine spread occurred even without deep
myometrial invasion.
The term clear-cell carcinoma was first defined by Scully
and Barlow [57], who described tumors that originated from
the Mullerian epithelium. Under microscopy, the tumors
show tubulocystic, papillary, or solid patterns; can have a
clear appearance because of their high glycogen content (and
not intracellular mucin); and sometimes include eosinophilic
cells and hobnail cells (Fig. 12). Sometimes, there is a
transition from serous and clear-cell histology in the same
Fig. 7. Hypothetic model of the pathogenesis of type 1 EC (see text).
Fig. 8. Villoglandular type of endometrioid endometrial adenocarcinoma: papillary growth with thick fibrovascular cores covered by well-differentiated (A, B)
and moderately differentiated (C and D) endometrioid type epithelium. (Immunhohistochemistry represented p53 negativity and strong nuclear staining for
estrogenoeus receptor analysis in both cases.) Compare these features with Fig. 11.
304 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
tumor. In patients receiving exogeneous progesterone
therapy because of irregular bleeding symptoms, foci of
clear cells mimicking Arias-Stella phenomenon may be seen
[11]. This feature may cause problems in the differential
diagnosis to clear-cell carcinoma, but immunohistochemistry
might be helpful.
Like uterine serous carcinoma, clear-cell carcinoma has
low expression of estrogen and progesterone receptors. p53
expression is intermediate between those reported in uterine
serous carcinoma and those in endometrioid cancers [58].
The rarity of clear-cell carcinoma precludes randomized data
on treatment outcomes; however, these tumors sometimes
respond to chemotherapy.
8. Rare endometrial carcinomas
Primary squamous-cell carcinoma of the endometrium
is quite uncommon. In a retrospective review of 1182
patients with corpus cancers, 6 (0.5%) had squamous-cell
carcinomas [59]. The diagnosis requires careful examina-
tion of the uterus to rule out the presence of a component
of adenocarcinoma or adenosquamous carcinoma and
to exclude a connection between the squamous-cell
carcinoma in the corpus and the squamous epithelium of
the cervix uteri [14]. On histology, there must be a clear
evidence of squamous differentiation on hematoxylin and
eosin staining, such as intercellular bridges and/
or keratinization.
Recent results have suggested that primary endometrial
squamous-cell carcinoma (Fig. 13) is not estrogeneous-
dependent and that alterations of the p16 pathway (without
any association to HPV infection), but not of the p53
pathway, may play a role in their pathogenesis [60,61]
(Horn et al, unpublished results). Chronic endometritis,
Fig. 9. Endometrioid type endometrial adenocarcinoma from minimal
deviation type: deep infiltration of irregular-shaped endometrial glands
within the myometrium (A). Glands are lined by well-differentiated
endometrioid type epithelium and surrounded by strong desmoplastic
changes (B).
Fig. 10. Hypothetic model of the pathogenesis of type 2 EC (see text).
Fig. 11. Serous carcinoma of the endometrium: complex papillary
architecture with small papillae with smooth fibrovascular cores (A) that
are covered by very hyperchromatic nuclei. Note the exfoliated tumor cells
within the papillae. Compare these features with Fig. 8.
305 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
hypovitaminosis A, estrogen deficiency and senile involu-
tion, presence of chemicals in the uterus as well as
previous irradiation are considered pathogenetic factors of
squamous metaplasia of the endometrium [60,61]. The
prognosis is closely related to type 1 endometrial
carcinoma [59,62].
Primary transitional cell carcinoma of the endometrium
is a rare, distinct subtype of endometrial carcinoma with
morphologic features of urothelial differentiation, which
reveals about 20 cases described to date. Immunohisto-
chemistry demonstrated a similar immunoprofile to
endometrioid carcinoma of the endometrium [63,64].
The prognosis is probably similar to type 1 endometrial
carcinoma [63,65].
Sertoliform endometrioid carcinomas represent a sub-
group of endometrioid adenocarcinomas with a pattern
resembling that of ovarian Sertoli cell tumors [66]. They are
composed of small hollow tubules, lined by columnar cells
with apical, occasional clear cytoplasm and short, slender
cords. These cells are immunoreactive for cytokeratines,
EMA, and vimentin, but negative for actin or desmin. Based
on the small number of cases, the behavior may not differ
from type 1 EC [67].
Neuroendocrine carcinomas of the endometrium may
rarely occur as small and large cell neuroendocrine tumors.
Small-cell neuroendocrine carcinoma of the endometrium is
extremely rare [68,69]. On hematoxylin and eosin, the tumor
resembles neuroendocrine features. Immunohistochemical
evidence of neuroendocrine differentiation can be demon-
strated using neuron-specific enolase and synaptophysin. The
clinical behavior of this tumor is usually very aggressive [70].
Large-cell neuroendocrine carcinoma may occur in the
endometrium [71]. They represent similar morphologic
features like large-cell neuroendocrine carcinomas at other
sites and are also associated with a poor prognosis.
9. Mixed endometrial carcinomas
About 10% of endometrial carcinoma show a mixed
histology [72,73], that is, at least one other component
comprising at least 10% of the tumor is present. Cirisano et al
[56] reported that at least 25% of uterine serous carcinoma or
clear-cell carcinoma that present with mixed histology had a
clinical behavior comparable to that of type 2 carcinoma. In
the study of Boruta et al [53] (see above), there was a trend
Fig. 12. Clear-cell carcinoma: solid sheets with sometimes papillary growth
pattern of cells with abundant clear cytoplasm and central location of
irregular-shaped nuclei.
Fig. 13. Primary squamous-cell carcinoma of the endometrium: solid
tumor growth with insular pattern of irregular tumor cells with features
of keratinization.
Fig. 14. Adenocarcinoma with squamous-cell differentiation: well-differ-
entiated endometrioid type adenocarcinoma with morule-like squamous
differentiation (A). Note the benign appearance of the squamous cells.
Adenosquamous carcinoma (B) representing infiltrative growth of both the
glandular and squamous part of this tumor.
306 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
toward a worse prognosis when serous carcinoma comprised
even 10% of the whole tumor.
In a recent review, it has been pointed out that for serous
carcinoma with additional choriocarcinomatous differentia-
tion, the choriocarcinomatous component in patients is life-
threatening, and metastatic disease occurs very rapidly [74].
Consequently, the clinical course is more rapid and often
fatal. However, the disease can be managed with chemother-
apeutic regimens used in (high-risk) gestational trophoblastic
disease [74].
Therefore, treatment approaches for tumors of mixed
histology, when an aggressive variant is present, are similar
to those for type 2 EC or choriocarcinoma.
Adenocarcinoma of the endometrium with squamous-cell
differentiation was traditionally regarded as a tumor with
mixed histology. Pekin et al [75] reported a frequency of
about 20% for adenoacanthomas (ie, endometrioid adeno-
carcinoma with benign appearing squamous-cell metaplasia)
and of 6% for adenosquamous carcinomas (in which the
squamous component resembles a squamous carcinoma)
(Fig. 14). It has been reported that endometrioid carcinomas
and adenocarcinomas with squamous-cell differentiation
represent a similar prognosis [62,75,76]. So, the prognosis
is dependent on the grade of the glandular component as well
as the stage of the disease.
10. Tamoxifen-associated endometrial lesions
Patients with hormone receptorpositive breast cancer are
routinely treated with the antioestrogenic drug tamoxifen
(TAM). Several reports have shown the development of
endometrial pathologies, including cancerous lesions, under
the use of TAM [77,78]. It is well known that there is no
close correlation between the endometrial thickness and
endometrial pathology [79]. Endometrial polyps are the most
common endometrial lesions in patients receiving TAM
[78,80]. Interestingly, the glands of endometrial polyps from
women treated with TAM represent a decreased expression
of estrogen receptor but a comparable increase of progester-
one receptor [81] (Horn et al, unpublished results) and an
increased p53 expression (Fig. 15; Horn et al unpublished
results). The pathogenetic aspects of endometrial lesions
under TAM therapy are hypothesized in Fig. 16. There is a
trend for an increase of mucinous tumors under TAM
treatment (Fig. 17). Mucinous carcinomas constitute about
5% of all cases of uterine carcinoma; it is rarely found as a
pure cell type [82]. Early-stage mucinous carcinomas seem
to have a similar prognosis to more common endometrioid
endometrial carcinomas and are managed similarly.
At the moment, there is increasing evidence that the risk
of EC in women using TAM is only slightly increased and
that there is no association with aggressive histopathologic
variants [83,84].
11. Endometrial lesions in patients with hereditary
nonpolyposis colorectal cancer syndrome
The Lynch syndrome (hereditary nonpolyposis color-
ectal cancer) is an autosomal dominant cancer susceptibility
syndrome caused by a germ-line mutation in one of the
DNA mismatch repair genes. It is associated with an early
onset of cancer and the development of multiple types of
Fig. 15. Hypothetic model of the pathogenesis of EC, associated with TAM
treatment in patients with breast cancer (see text).
Fig. 16. Immunohistochemical steroid hormone receptor analysis of cystic endometrial polyp in patients without and with TAM treatment. ER indicates
estrogeneous receptor; PR, progesterone receptor.
307 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
cancer, including cancer of the colon and rectum,
endometrium, ovary, small bowel, ureter, and renal pelvis.
The lifetime risk of EC for women with the Lynch
syndrome is 40% to 60% [85], which equals or exceeds
their risk of colorectal cancer. Most cancers diagnosed in
women after the age of 35 and prophylactic surgery might
be of benefit in those patients [85]. Vasen et al [86]
evaluated the lifetime cancer risks associated with different
gene mutations in 138 families in which the Lynch
syndrome occurred. They found the risks of both EC and
ovarian cancer to be higher in MSH2 mutation carriers than
in MLH1 mutation carriers, but the differences were not
statistically significant. At times, there is no evidence for
the occurrence of highly aggressive variants of endometrial
carcinomas in patients affected by hereditary nonpolyposis
colorectal cancer [87], but mixed type 1 and type 2
endometrial carcinomas have been reported [88].
12. Handling surgical specimens from the endometrium
Careful handling and microscopic examination of
endometrial specimen resulted from curettings and hyster-
ectomy are recommended to establish the correct (intrao-
perative) diagnosis, which represents the basis for any
therapeutical decisions.
Material from fractional curetting should be separately
processed in different blocks, one representing the
material obtained from the cervix uteri and the other
ones representing the material from the corpus. All tissue
from the cervical part should be embedded completely
as done with the material from the uterine corpus up to
3 cm. The material from curettings must be examined
very carefully, especially the cervical part for the occur-
rence of infiltration of endometrial carcinoma into the
cervical glandular lumina (FIGO IIA) or into the cervical
Fig. 17. Endometrial carcinoma in a patients receiving TAM: note the
mucinous differentiation in this well-differentiated tumor (A). On
immunohistochemistry, the tumor cells are negative estrogeneous receptor
analysis (B) but represent strong positive reaction for progesterone
receptor (C).
Fig. 18. Fragments of well-differentiated endometrioid endometrial
carcinoma in the cervical part of a fractional curetting (A) without any
infiltration of endocervical mucosa (B). The atypical glands are dislocated
from the endometrial tumor by irregular bleeding. There are no features for
FIGO stage II disease (see text).
308 L.-C. Horn et al. / Annals of Diagnostic Pathology 11 (2007) 297311
stroma (FIGO stage IIB). In the most cases, the endo-
metrial carcinoma in the cervical part of a fractional
curetting is dislocated from the endometrium by operation
procedure or lies in the cervical channel because of
irregular bleeding as the leading symptom of endometrial
neoplasias. If the direct invasion of the above-mentioned
structures cannot be determined, the diagnosis of stage II
disease is avoided (Fig. 18).
Hysterectomy specimens with endometrial carcinoma
are often submitted for frozen section to determine the
depth on invasion [89]. There is a good correlation
between the determination of the depth of invasion by
frozen section and permanent section analysis [90] with a
sensitivity of frozen section of 85% and specificity of
about 100% [91]. However, in most cases, the clinicians
ask for the involvement of the cervix uteri and the ovaries.
So, the cervix and both ovaries should be examined
macroscopically very carefully. In any suspicious or
doubtful cases, additional frozen section from these sites
should be performed. The assessment of tumor grade by
frozen section should be performed only in selected cases
by gynecologic pathologist.
The pathologic examination of the uterus and adnexa is
necessary for final staging on the postoperative specimen
[92]. In that process, the weight and the size of the uterus and
adnexa should be given. The appearance of the serosal
surface, the myometrium, and the uninvolved endometrium
should be described. The uterine tumor should be described
for its location (fundus, right/left cornu, isthmus), its 3-
dimensional size (length, width, thickness), its distance from
the margins and from the external os, its descriptive
characteristics (eg, exophytic, necroses, color), its estimated
depth of infiltration into the myometrium, and its infiltration
of the cervix. All additional findings should be recognized
(eg, uterine leiomyomas). Both adnexa should be measured
with additional description of the serosal surface and the
cutting surface.
A scheme for obtaining tissue for histologic examina-
tion is given in Fig. 19. The serosal surface may be inked
at the area of deepest myometrial invasion. One block per
largest tumor dimension should be obtained for histologic
analysis. A separate block form the endocervix should be
obtained to establish if there is a cervical involvement on
histology or not. If possible, the entire adnexae (ovaries
and tubes) should be processed in all cases. Because of
the fact that metastases reach adnexal tissue via
lymphatics and blood vessels, mesovarian and mesosal-
pingeal tissue should be included in the blocks, obtained
from the adnexae.
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