Demystifying endometrial

hyperplasia
Efthimios Sivridis
Alexandra Giatromanolaki
Abstract
The endometrial hyperplasias form a spectrum of proliferative lesions, not
all of which conform to conventional denition of hyperplasia. For whilst
most hyperplastic lesions are composed of cells normally occurring in the
late proliferative phase endometrium, there are those few which consist
of genuine atypical cells. Lesions of this type, so-called atypical endome-
trial hyperplasias, tend to merge imperceptibly with well differentiated
endometrioid adenocarcinomas, giving rise to major challenges: First
and foremost, what are the very essential criteria that should be met
before diagnosing such a lesion? And what are the very least that should
be insisted upon for diagnosing malignancy once an atypical endometrial
hyperplasia has been established? What is its true nature and how should
ideally be classied? Other less conicting, but equally interesting, as-
pects of endometrial hyperplasia which are covered in this account
include the conventional hyperplasias, i.e. those lacking cytological aty-
pia, and the overall incidence, risk factors and treatment of the disease.
It is worth noting that pure stromal cell proliferations are, in itself, not
necessarily neoplastic, for many take the form of endometrial stromal
hyperplasia.
Keywords atypical endometrial hyperplasia; classication; endometrial
hyperplasia; endometrial intraepithelial neoplasia (EIN); endometrial
stromal hyperplasia
Introduction
The endometrium, a target tissue for sex-steroid hormones,
consists of two main structural components e the endometrial
glands and the specialized endometrial stroma. As part of its
physiological function, these two elements proliferate and grow
under the inuence of ovarian oestrogens (rst half of the
menstrual cycle), a proliferation which would only cease with
the antagonistic effect of progesterone which induces endome-
trial maturation and differentiation (second half of the menstrual
cycle). However, under certain pathological conditions, such as a
sequence of anovulatory cycles and granulosa cell tumours, this
periodic oestrogeneprogesterone secretion is disrupted in favour
of the former, and unopposed oestrogenic stimulation of the
endometrium pursues setting the stage for endometrial hyper-
plasia (EH) and/or neoplasia.
As it would be expected, most cases of EH arise from both
glands and stroma (simple hyperplasia), with the overall cellular
elements to produce what is in effect an exaggeration of the
normal proliferative phase endometrium.
1
However, not all
endometrial hyperplasias (EHs) show this typical pattern and
many assume a hyperplastic growth which involves exclusively
glands, with crowding and branching, but certainly without
cytological atypia (complex hyperplasia). The above two growth
patterns appear to conform with the usual stereotype of a hy-
perplasia without crossing the boundaries of neoplasia.
Hyperplasia is, in general terms, the increase in size of an
organ or tissue as a result of an increase in the number of
specialized cells per reference area or volume. The lesion is
benign and the hyperplastic cells are, essentially, similar to
normal or may appear slightly enlarged (hypertrophic). Genuine
hyperplastic lesions, including those of the human endometrium,
very rarely, if ever, progress into malignant disease. Yet, endo-
metrial adenocarcinomas, particularly those of the endometrioid
cell type (EACa), may at times preceded by a form of proliferative
lesion which is composed exclusively of glands, often with
crowding and complexity, and always with nuclear and cyto-
plasmic atypia
1
; this condition, which is most commonly known
as atypical endometrial hyperplasia (AEH), may evolve into an
EACa with an incidence which is too high to be dismissed as
coincidental.
The endometrial hyperplasias e the WHO classication
The term endometrial hyperplasia covers a spectrum of pro-
liferative lesions in the endometrium some of which progress to
or co-exist with endometrioid adenocarcinoma (EACa). There is,
in general, good correlation between a particular histological
type and the consequent biological behaviour of the lesion.
However, this relationship between histological appearances and
prognosis has been blurred by inconsistencies in terminology
and denitions. Indeed, diagnostic terms like atypical,
adenomatous, adenomatoid, complex and irregular hy-
perplasia have been used in a highly subjective manner to hy-
perplastic lesions of the endometrium having and having not a
signicant risk of progressing into an EACa.
2
Other diagnostic
labels which have been applied to hyperplastic lesions in the past
and which denote some malignant potential include atypical
glandular proliferation, atypical epithelial proliferation,
glandular hyperplasia with architectural atypia and glandular
hyperplasia with cellular atypia. Further, the term hyperplasia
was applied without qualication by some workers to any form
of endometrial hyperplasia irrespective of specic histological
characteristics. This widespread confusion was reduced consid-
erably with the introduction of an internationally agreed classi-
cation, that of the World Health Organization (WHO) 1975, as
revised by WHO and the International Society of Gynecologic
Pathologists (ISGYP)
3
in 1994.
According to this classication, the EHs are independently
assessed for their architectural and cytological features. Thus, the
glandular architecture can be either simple or complex: it is
Efthimios Sivridis MD PhD Emeritus Professor in Pathology,
Department of Pathology, Democritus University of Thrace Medical
School, and University General Hospital of Alexandroupolis, Greece.
Conicts of interest: none declared.
Alexandra Giatromanolaki MD Professor in Pathology, Department of
Pathology, Democritus University of Thrace Medical School, and
University General Hospital of Alexandroupolis, Greece. Conicts of
interest: none declared.
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simple when the glands are widely spaced and have a smooth
rounded outline, and it is complex when the glands are
crowded and show multiple branchings into the surrounding
stroma. The cells lining the endometrial glands are assessed as to
whether are truly hyperplastic, i.e. normal in appearance
(perhaps slightly enlarged), or whether they are atypical, i.e.
display features which are obviously abnormal.
This approach results in four diagnostic categories of endo-
metrial hyperplasia: simple hyperplastic, complex hyperplastic,
simple atypical, and complex atypical. Since atypical hyperplasia
with a simple glandular architecture is fairly rare and onomato-
logically may be confused with SEH, many pathologists employ
the term atypical hyperplasia to include cases of both simple and
complex atypical hyperplasia. As a result, the following forms of
endometrial hyperplasia are commonly used in practice:
Simple hyperplasia;
Complex hyperplasia;
Atypical hyperplasia (simple and complex).
Note that these forms may occur separately or in any com-
bination within a single endometrial biopsy.
The simple endometrial hyperplasia (SEH)
This is the most common form of endometrial hyperplasia,
occurring mainly at the perimenopause e an immediate sequence
of anovulatory cycles. It is also the most genuine form of hyper-
plasia as the endometrium, in response to continuous oestrogenic
stimulation, assumes a pattern of proliferative activity which in-
volves both endometrial components, i.e. the glands and the
stroma e as a result the normal gland to stroma ratio is main-
tained and there is no crowding of the glands. Further, the hy-
perplastic process is diffuse and affects the entire thickness of the
endometrium, which loses the distinction between basal and
functional layer and assumes a bulky and often polypoid
appearance. The feature that stands out, however, is the great
variability in the size and shape of the proliferating glands as
many are large and cystic, probably with some epithelial budding,
whereas others are small and have a smooth rounded outline
(Figure 1). They are lined by normal columnar cells, having oval
or elongated nuclei, with obvious pseudostratication and an
amphophilic cytoplasm. Ciliated cells, usually in patches, and
vesicular or clear cells (large clear cells with a central nucleus
and abundant faintly staining cytoplasm), scattered among the
glandular epithelial cells, are increased in numbers, reecting an
excessive oestrogenic stimulation (oestrogenized epithelial cells).
The specialized endometrial stroma is conspicuously abundant
and hypercellular, with the stromal cells having oval to elongated
nuclei, scanty cytoplasm and ill-dened cell borders giving the
well-known appearance of naked nuclei. Mitoses are noted in
both epithelial and stromal cells. The spiral arteries are poorly
developed in SEH, but the supercial thin-walled venules are
prominent, and often dilated, congested or thrombosed, resulting
in focal haemorrhage and stromal necrosis. Accumulation of
polymorphs and focal areas of oedema are additional features.
The overall picture resembles normal late proliferative phase
endometrium, although the endometrial growth is more
exuberant. The association with EACa is less than 1% (between
0.4 and 1%)
4
e a gure which is in close approximation to that
which would be expected to occur by chance.
The complex endometrial hyperplasia (CEH)
Less commonly, the endometrial proliferations are focal and
restricted to endometrial glands. Hyperplasia of this type may
occur not only in the presence of prolonged unopposed oestro-
genic stimulation of the endometrium, whatever the cause, but
also in young women with normal menstrual cycles. Since the
stroma does not participate in the hyperplastic process, the gland
to stroma ratio becomes greater than normal and the glands
show crowding and architectural complexity, mainly in the form
of branchings rather than infoldings (Figure 2). The glandular
epithelium, however, remains blunt, composed of columnar
cells, with oval or elongated nuclei, having apparent pseudos-
tratication and occasional mitoses e a cytology that closely
resembles that of the normal late proliferative phase endome-
trium. The stroma between the hyperplastic glands is com-
pressed, but not obliterated, in so far as a thin rim of tissue
remains separating the glands. Elsewhere, the endometrium
Figure 1 SEH: cystic endometrial glands with pseudostratication, and
abundance of a dense cellular stroma (H&E 200).
Figure 2 CEH: focal glandular crowding and branching, but normal pro-
liferative type cells (H&E 200).
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remains normal, e.g. appropriate to the patients age and hor-
monal status. CEH has a <3% association with EACa.
4
The atypical endometrial hyperplasia (AEH)
There exists, however, a type of proliferative lesion in the endo-
metriumwhich bears all the hallmarks of nuclear and cytoplasmic
atypia, but which characteristically lacks stromal invasion. This
lesion is usually focal or multifocal in distribution and affects
exclusively glands. Architecturally, the glands tend to show
crowding, with a typical back-to-back arrangement, although a
thin rim of intervening stroma does remain in between; they also
show complexity in the form of multiple branchings and intra-
glandular infoldings or tufts lacking brovascular cores. The
condition has been variously termed atypical endometrial hy-
perplasia, carcinoma in situ, intraepithelial carcinoma,
intra-endometrial neoplasia (IEN) or endometrial intra-
epithelial neoplasia (EIN) and possesses a strong natural
tendency towards progression to EACa e indeed, between 22 and
52% of cases proceed to stromal invasion
4,5
over a mean period of
4e6 years; there is also a high incidence of co-existent EACa.
The essential criteria of recognizing cytological atypia and,
thus, by implication, the diagnosis of AEH, are given below, with
the vast majority of cases being accompanied by glandular
crowding and complexity forming glands of irregular outline
(complex AEH). In some cases, however, the glands exhibiting
cytological atypia are widely spaced and have a regular smooth
outline (simple AEH). Such lesions may be limited to a few
glands, sometimes to one or two, and sometimes only part of a
single gland may be affected.
What are the very essential criteria for diagnosing AEH?
It is apparent fromthe above descriptionthat the diagnosis of AEHs
rests solely on specic nuclear and cytoplasmic features,
1
whilst
the architectural pattern of the lesion is only of secondary impor-
tance. Thus, the dening cytological features of AEH are:
The presence of large nuclei, almost twice the normal size,
which are characteristically round, instead of elongated,
and vesicular rather than hyperchromatic, and which
usually contain one or more prominent nucleoli (Figure 3).
There must be loss of the normal nuclear polarity.
There must be loss of cell-to-cell and cell-to-basement
membrane cohesion. The loss of cellular cohesion, com-
bined with the loss of nuclear polarity, may allow atypical
cells to grow in syncytial-like aggregates, while the piling
up of such cells into irregular masses form small intra-
luminal papillae or tufts, lacking brous cores.
There should be abundant cytoplasm, with indistinct cell
borders, and intense eosinophilia.
Pseudostratication or true stratication of epithelial cells
usually accompany cytological atypia, but this feature is not
specic to AEH and may well occur, in other forms of EH.
There must be no evidence of stromal invasion.
How is AEH distinguished from a well-differentiated EACa?
There can be no doubt that myometrial invasion is the most
reliable criterion for separating EACa from AEH. Yet, detecting
this feature in a curettage specimen is a difcult, if not
impossible, task, and, under these circumstances, criteria
indicative of stromal invasion are sought.
1
In fact, a hyper-
plastic lesion exhibiting cytological atypia and any of the
following features, alone or in combination, merit being classi-
ed as EACa:
Small clusters of atypical epithelial endometrial cells or
atypical endometrial glands invading a newly formed
stroma (hyalinized and/or somewhat oedematous brosis)
(Figures 4 and 5).
A solid growth pattern formed by atypical endometrial
cells (not squamous or squamoid in type) (Figure 6).
Figure 3 AEH: Large rounded nuclei, often vesicular, with occasional
prominent nucleoli; there is also stratication with loss of nuclear polarity
and loss of cellular cohesion (H&E 1000).
Figure 4 A cluster of atypical epithelial cells invading a newly formed
stroma. Note also large round vesicular cells with abundant eosinophilic
cytoplasm with indistinct cell borders. There is also loss of polarity, loss
of cell-to-cell and cell-to-basement membrane cohesion, and papillary
tufts lacking brovascular cores. Compare the upper left portion of the
eld (atypical cells) with that of the lower right (cells within normal limits)
(H&E 400).
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The formation of giant tumour glands by merging of
individual glands having complete obliteration of the
intervening stroma e the so-called complex or
conuent glandular pattern (Figure 7) e an arrangement
which may, at times, take the form of a cribriform
pattern (Figure 8). Small intraluminal papillae/tufts of
atypical cells, without any stromal support but having a
tendency to fuse, may form intraglandular bridges and
exhibit a somewhat similar pattern (Figure 9).
The dominant presence of large, elongated and branching
papillary fronds, having brous cores, albeit rather thin e
a pattern commonly referred to as papillary (Figure 10).
A newly formed stroma (stromal brosis), even in the
absence of any demonstrable invasion, should alert the
pathologist to this possibility. Similarly, focal stromal ne-
crosis and the presence of neutrophils and nuclear debris
within glandular lumens may coexist with stromal inva-
sion, necessitating extensive sampling (embedding all the
material, deeper sections).
Aggregates of foamy histiocytes and the presence of squa-
mous morules or squamous differentiation are not, in general,
specic are not specic diagnostic features since they have been
noted in both EACa and AEH. Neither is mitotic activity in itself
of any particular value, given that the normal proliferative phase
endometrium contains more mitoses than AEH or an AECa; yet,
the rare presence of abnormal mitoses does suggest an invasive
disease.
What is the true nature of AEH?
The question as to whether the AEH is hyperplastic or neoplastic
in nature is less practical than to make its diagnosis or draw its
Figure 5 Atypical endometrial glands invading a newly formed stroma
(hyalinized and somewhat oedematous). Note a focus of solid growth
pattern in the upper right portion of the eld (H&E 200).
Figure 6 A solid growth pattern formed by atypical endometrial cells (H&E
200).
Figure 7 Stromal invasion in the form of a giant tumour gland e the
merging of adjacent endometrial glands with obliteration of the inter-
vening stroma (H&E 200).
Figure 8 Stromal invasion in the form of a cribriform pattern (H&E
200).
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distinction from an EACa, but it is certainly equally interesting.
The existence of such a lesion as a histological entity and its
irreversible commitment to neoplasia was rst noted by Thomas
Cullen
6
in 1900 and accumulated evidence since that date have
indicated that AEH is probably a form of endometrial neoplasm
e a view which is clearly reected in its various designations
given by several workers (see: The atypical endometrial hy-
perplasia). There are also those who equate AEH with a well-
differentiated endometrial adenocarcinoma of the endometrioid
type (EACa) by the name of endometrioid neoplasia (EN).
7
The
term atypical hyperplasia (AEH), which was adopted by the
WHO, may probably not be universally accepted as expressing
the true nature of the disease, but it does not either contradict to
the theory of neoplastic development as dened by Jacob Furth
8
:
Neoplasms are a heterogeneous group of diseases; they range
from uncontrolled hyperplasia through hormone-responsive
neoplasia to autonomous neoplasia. But what is the available
evidence in support of a neoplastic rather than hyperplastic
origin of AEH?
Firstly, it is the histology of the lesion; this is identical to or
indistinguishable from an EACa.
Secondly, it is the electron microscopy of AEH; this shows
a morphological continuum of abnormalities with EACa.
Thirdly, it is the continuous growth of the lesion; AEH will
not revert to normal when the oestrogenic stimulus which
initiated proliferation is withdrawn.
Fourthly, it is the natural history of the disease; atypical
endometrial hyperplasia, if left untreated, progresses to
invasive endometrial adenocarcinoma with a frequency
over 52%.
5
Furthermore, many cases (42.6%) with a
diagnosis of AEH on endometrial biopsy often co-exist with
endometrial malignancy (EACa) in the hysterectomy
specimen.
9
Fifthly, it is the common molecular genetic changes; these
include inactivation of PTEN tumour suppressor gene,
microsatellite instability,
10
and the activation of K-ras
genes.
11
None of the above aberrations are shown in
simple or complex endometrial hyperplasia.
Last but not least, it is the autophagic activity in the form of
stone-like structures (SLS); these are compact and dense,
spheroidal cytoplasmic structures, 5 mm on average, which are
enclosed within cytoplasmic vacuoles; they encountered exclu-
sively in epithelial neoplastic lesions, including EACas, but do
also occur in AEH.
12
Other classication schemes of endometrial hyperplasia
The World Health Organization (WHO) classication of endo-
metrial hyperplasia is now the most widely used system.
3
This
classication, based on the classical study of Kurman et al.,
4
is
useful in practice and has a considerable merit with respect to
prognosis. Furthermore, by providing an internationally agreed
terminology, the scheme was aimed to end the confusion sur-
rounding denitions and nomenclature of EH.
Despite this, the WHO classication has been criticized for
complexity and low level of reproducibility; in particular, the
assessment of nuclear atypia was considered as being highly
subjective resulting in marked interobserver variation.
7,13,14
This, however, has not been everyones experience
15
and
certainly not ours, but we must admit that the accurate identi-
cation of AEH and its distinction from a well differentiated EACa
often presents difculties.
In line with these thoughts, Bergeron et al.
7
proposed the
amalgamation of AEH with EACa in a single diagnostic category
so-called endometrioid neoplasia (EN); when their series was
studied in this manner they found an increase in reproducibility,
relative to the WHO classication, but their sample was too small
(16 cases of EACa and 6 cases of AEH) for any rm conclusions
to be drawn. In the same study, simple and complex endometrial
hyperplasia were combined by the name of hyperplasia.
Earlier Skov et al.
13
had divided endometrial hyperplasias into
those having cytological atypia (AEH) and those lacking this
feature (combined SEH-CEH) and succeeded in improving the
overall agreement of the WHO 1975 and 1994 classications. It
should be noted, however, that although this approach is, in it-
self, of undoubted clinical importance, the results obtained need
Figure 10 A typical papillary pattern of invasion (H&E 200).
Figure 9 Stomal invasion by forming intraglandular bridges of atypical
cells, without any stromal support. Note also the merging of individual
glands (H&E 200).
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verication for transitional forms between SEH and CEH are not
seen, even when both are present in the same endometrium,
and often there is a very sharp and clear boundary between the
two abnormal patterns.
1
Following an essentially similar strategy, Mutter and the
Endometrial Collaborative Group (ECG)
16
used the name benign
endometrial hyperplasia to include hyperplasias of both simple
and complex form, and redened AEH in terms of molecular,
morphometric and morphological criteria; the condition, which
was designated endometrial intraepithelial neoplasia (EIN)
would not be diagnosed unless it satises the following criteria:
A monoclonal growth.
A size greater than 1 mm in diameter or more than ten
glands.
Closely packed glands, with a gland area exceeding that of
stroma (volume percentage stroma <55%).
Cytological change that is always different from that of the
adjacent normal endometrium.
Exclusion of benign conditions.
Exclusion of EACa.
With the application of these criteria which, by denition, will
have to be taken in their entirety, Mutter and the ECG
16
noted an
increase in reproducibility of the WHO94 classication, but their
claim was substantiated only by afliated groups of workers;
data derived from independently reported studies indicated that
the WHO and EIN classications are equally satisfactory in terms
of reproducibility,
5,17
frequency of co-existent EACa
18
and ex-
pected risk of progression to EACa,
19
the latter sometimes being
more satisfactory by the application of the WHO system.
20
Others found that the most effective scheme in improving
interobserver reproducibility of the WHO94 classication is that
which divides EHs into: SEH and less severe forms (negative,
disordered proliferative endometirum) versus CEH and more
severe forms (AEH and EACa).
21
They reached this conclusion
after testing various binary systems.
These somewhat controversial results have prompted a thor-
ough re-evaluation of the design and the criteria used in these
studies.
2
Thus, the overall strategy to improve reproducibility of
the WHO94 classication by reducing the four categories to
two
7,13,16,21
it would seem to us simplistic rather than simple, for
any contraction of the number of diagnostic choices would
compromise the evolution of the scientic knowledge, not
infrequently, at the expense of the patients care
15
; a hypothetical
acceptance of the concept of endometrioid neoplasia,
7
for
example, would lead to overtreatment.
With regard to the validity of the EIN criteria, this deserves
more than a passing comment. Thus, monoclonality (a most
important feature in the EIN classication)
16
is only suggestive,
but not conclusive, of endometrial neoplasia as it occurs with
greater frequency in simple endometrial polyps, endometriotic
cysts and in CEH without atypia; in the small sample of Mutters
et al. study
16
only two of the four AEH were monoclonal. Neither
a size of greater than 1 mm
2
in diameter nor an increased gland
to stroma ratio are, in themselves, evidence of neoplasia: lesions
smaller than 1 mm
2
occur early in neoplastic disease; glandular
crowding is the sine qua non of CEH, whilst many AEHs (EIN) or
EACas may not conform to this stereotype. The exclusion of
other conditions that present with abnormal uterine bleeding,
particularly EACa, is self-evident, but it is worth reiterating here
that whilst the premalignant lesions (AEH or EIN) lack clear
evidence of stromal invasion, they do display cytological atypia
which often is more pronounced than that of an invasive EACa.
1
The importance of this feature, initially blamed as being highly
subjective for diagnosing AEH by the ECG,
16
it has now gained
acceptance by the self-same proponents of the EIN taxonomy
who withdrew monoclonality in favour of the standard H&E
slides viewed through a routine microscope.
22,23
For, indeed,
any difculty with the denition of cytological atypia should be
resolved by improving the diagnostic skills of the students of
endometrial pathology.
15
Clinical features, aetiopathogenesis and treatment of endometrial
hyperplasia
Endometrial hyperplasia is a prevalent gynaecological disease
that affects women from menarche to 75 years and over. In the
United States the overall incidence of endometrial hyperplasia
(simple, complex and atypical) is 133 per 100,000 women per
year
24
; it is most common in women ages 50e54, and is rarely
observed in women under 30 (6 per 100,000 woman per year).
24
The disease is usually detected following investigation of
abnormal uterine bleeding. The imaging technique most
frequently employed for assessing the endometrium, particularly
in postmenopausal women, is transvaginal ultrasound. A mean
endometrial thickness of >5 mm may indicate the presence of
pathology and requires endometrial biopsy or endometrial
curettage.
From a pathogenetic perspective, any condition resulting in
prolonged (more than ve years) oestrogenic stimulation of the
endometrium unopposed by progesterone action, whether
endogenous or exogenous, may cause endometrial hyperplasia.
By far the commonest endogenous factor is repeated anovulatory
cycles. These occur frequently during the perimenopause, and in
women with polycystic ovary syndrome, ovarian cortical hy-
perplasia or oestrogen-secreting ovarian tumours (granulosa-
theca cell tumours) e conditions in which there is usually an
excess production of androstenedione by the adrenal glands and
the ovarian stroma. Androstenedione is converted to oestrone in
the adipose tissue and leads to a persistently hyperoestrogenic
state.
Exogenous risk factors include the long-term administration
of noncyclical oestrogens for the relief of menopausal symptoms
(estrogene replacement therapy) and the treatment of breast
cancer with the synthetic hormone Tamoxifen; this has an anti-
oestrogen effect on the breast, but a pro-oestrogen effect on the
uterus. In addition, women with the Lynch syndrome II (hered-
itary non-polyposis colon cancer) are at a greater risk of devel-
oping endometrial hyperplasia and neoplasia.
Obesity plays a major contributory role in the development of
endometrial hyperplasia and carcinogenesis by increasing the
levels of circulating oestrogens. This may be the result of accel-
erated conversion of androstenedione to estrone or a decrease in
the levels of sex hormone-binding globulin (SHBG), the former
occurring with considerable frequency. The conversion takes
place in the adipose tissues by the enzyme cytochrome p450
aromatase and increases with increasing body weight (increased
numbers of fat cells) and with advanced age (increased specic
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aromatase activity). Interestingly, the factors of ageing and
obesity appear to be additive.
Other oestrogen-related factors which may provide an added
growth stimulus to the endometrium include the reduction
in average parity, the early onset of menarchy and the late onset
of menopause, which increase the life-time exposure of the
endometrium to endogenous oestrogens, and the presence of
diabetes and hypertension, although probably only among obese
women.
With regard to treatment, it is generally agreed that EHs
without cytological atypia should be treated with progestins
alone. It is also agreed that the primary mode of treatment for
patients with AEH is by surgical excision, although high-doses of
progestins for a duration of no less than six months may be
offered to young women who wish to retain fertility.
New perspectives
This account on endometrial hyperplasia would not be complete
without considering a rather under-recognized hyperplastic
process which does occur in the endometrium and which spe-
cically affects the endometrial stroma; it is the so-called focal
endometrial stromal hyperplasia. The existence of such a
lesion challenges the traditional view that endometrial pro-
liferations, consisting solely of stromal cells, are invariably
neoplastic. It is worth recalling here, that all proliferative lesions
in the endometrium arise from two main structural components,
the endometrial glands and the endometrial stroma, either of
which, alone or in any combination, have the potentiality to
undertake intense proliferation and growth affording three
possible morphological patterns: (i) proliferation of both glands
and stroma, (SEH), (ii) proliferation that is restricted to the
endometrial glands (CEH, AEH, EACa), and (iii) proliferation
restricted to the endometrial stroma e a pattern which, by
convention, it has been taken as being invariably neoplastic
(endometrial stromal nodule, low-grade endometrial stromal
sarcoma, undifferentiated sarcoma), but which recent evidence
indicates that may at times be hyperplastic.
For indeed, EHs consisting solely of stromal cells were only
exceptionally reported in the literature,
25
largely because these
lesions are not considered as a pathological entity distinct from
the endometrial stromal nodule and the low-grade endometrial
stromal sarcoma. Stewart et al. reported the rst recognized
hyperplastic lesion of endometrial stromal cells,
25
and three
similar cases were reported from our own laboratory recently.
26
Endometrial stromal hyperplasias are invariably of small
size (0.2e0.8 mm diameter), intra-endometrial in localization,
multifocal in distribution, and have a tendency to become
polypoid or to localize in a pre-existing polyp. They are formed of
small uniform spindle-shaped cells of increased cellularity, hav-
ing a remarkable similarity with the normal proliferative type
stroma. There is lack of cytological atypia, mitotic activity or
vascular invasion. Immunohistochemically, the stromal cells are
usually positive for CD10, vimentin, oestrogen and progesterone
receptors, but are negative for smooth muscle actin, desmin and
usually for c-kit.
27
A specic molecular genetic change is the
translocation t(6;14)(p21;q24). The possibility of an endometrial
stromal nodule or a low-grade endometrial stromal sarcoma
should always be excluded. Features favouring neoplasia include
a single circumscribed nodule of large size (4 cm on average)
which, not infrequently, lies in the myometrium. The histology of
such lesions, although resembles a normal proliferative or hy-
perplastic stroma, may reach a mitotic rate of up to 10 per high-
power elds, and there is fusion of the gene JAZF1/JJAZ1 caused
by a t(7;17)(p15;q21) translocation.
27
Conclusion
This discussion indicates that the human endometrium responds
to unopposed estrogenic stimulation in three different ways: by
proliferation of both glands and stroma (SEH), proliferation of
only the endometrial glands (CEH, AEH, EACa) and/or by pro-
liferation of only the endometrial stroma (STH, endometrial
stromal neoplasms). SEH is the most common form of patho-
logical proliferation in the endometrium, representing a genuine
hyperplastic lesion. CEH and STH are also hyperplastic lesions,
though less typical, in the sense that only one of their two main
structural components are proliferating. AEH is probably a
neoplastic (precancerous) lesion having a high incidence of
progression to EACa. It should be separated from the other forms
of hyperplasia by the presence of nuclear and cytoplasmic atypia,
and from EACa from the lack of myometrial and/or stromal in-
vasion. Stromal hyperplasia should be distinguished from
endometrial stromal nodule and other stromal neoplasias from
its small size, intraendometrial location, the multiplicity of the
lesion and its lack of invasion. A
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