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EARLY DIAGNOSIS OF
ENDOMETRIAL CANCER
Liane Deligdisch
INTRODUCTION
Endometrial cancer is the most common malignant tumor of the
female pelvis in the US and in most parts of the Western world. Its
high incidence is related to the increased longevity, high fat diets,
hormone replacement therapy, and prolonged estrogenic stimulation, both exogenous and endogenous (of which obesity is the
most common). It is the fifth most common cancer of women in
the US. Hormone therapy is widely used throughout the world and
the histopathologic changes of the uterus, especially of the
endometrium in women treated with hormones encompass a variety of morphologic features which are often difficult to interpret.
The assessment of such changes in terms of precancerous potential
is challenging since the endometrium is one of the most sensitive
target tissues to hormone stimulation and can display structural
features suggestive of, but not necessarily representing endometrial
neoplasia.
149
4
CHAPTER
Endometrial carcinogenesis is generally considered to be related
to metabolic and hormonal anomalies. Other factors are also
involved, operating at a molecular genetic level that were recently
explored and seem to involve different carcinogenic pathways.
The prognosis of endometrial carcinoma, as in most cancers, is
closely related to the early diagnosis either of precancerous lesions or
of early invasive cancer, the survival rates being very different from the
cases detected in late stages.
The precursors of endometrial carcinoma consist of endometrial
hyperplasia, especially atypical glandular hyperplasia or endometrial
intraepithelial neoplasia (EIN) and endometrial in situ carcinoma
(EIC). Early endometrial carcinomas are endometrioid and nonendometrioid.
PRECURSORS OF ENDOMETRIAL CARCINOMA
The endometrium is endowed with a remarkable capacity to translate
hormonal stimulation into structural changes due to the presence of
receptors in the nuclei and the finely tuned mechanism of steroid
receptor binding to the cellular cytoplasmic organelles and their transfer to the nuclear receptor sites.
Estrogenic stimulation is translated by the target cells in the
endometrial glands into epithelial proliferation, which takes place during the reproductive period in life, followed by secretory changes
induced by the progesterone secreted by the postovulatory corpus
luteum. Continuous unopposed estrogen secretion elicits a continuous proliferation of the endometrial tissue, especially its glandular
compartment, with hyperplastic changes that may increase in severity
from simple, cystic, to complex, and atypical.
The diagnosis of endometrial hyperplasia is based on histopathologic examination. With the increasing degree of severity of the
hyperplasia, the reversibility of these changes decreases. Simple, cystic, and even complex glandular hyperplasia often revert to normal
under progesteronic stimulation. Complex glandular hyperplasia with
atypia may progress to endometrial carcinoma and is therefore considered a premalignant lesion.
150 L Deligdisch
Endometrial hyperplasia is seen most often in peri and postmenopausal women with progressively failing ovulation. But it can
also be present in younger women. It is associated most often with
obesity and/or polycystic ovarian disease, causing anovulatory
cycles, and occasionally, with ovarian sex cord stromal tumors. In
most cases in perimenopausal women, hypersecretion of steroid hormones by the ovary and/or adrenal cortex is converted to estradiol,
estrone, and estriol, of which estradiol is the most stimulating
because of its abundant receptor sites in the nuclei of the endometrial tissue. In postmenopausal women, the androgenic hormones
secreted by the ovaries and adrenal cortices can be converted into
estrogens as well and continue the estrogenic stimulation of the
endometrium. Obesity, diabetes, and other metabolic diseases may
enhance the extragonadal endogenous estrogen production by
aromatization.
In addition to the endogenous hyperestrogenic stimulation, the
effect of estrogenic substitution therapy used frequently for alleviating menopausal symptoms represents a common cause of endometrial
hyperplasia. Less commonly, young women who are treated with
estrogens for premature ovarian failure or congenital sexual gonadal
maldevelopment such as Turner’s syndrome may develop endometrial
hyperplasia and neoplasia.
The addition of progesterone to the estrogen therapy is meant to
imitate the natural effect of ovulation on the endometrium. However,
this combined therapy does not always produce the expected effect of
inhibiting all proliferation, probably because of the irregular distribution of progesterone receptors in the postmenopausal endometrium.
2
Endometrial hyperplasia is often associated with irregular vaginal
bleeding, which is fortunate because it brings the patient to medical
attention. Actually, any postmenopausal bleeding should be suspected
as due to neoplastic changes unless proven otherwise, therefore
endometrial biopsy is mandatory. At biopsy, it turns out that vaginal
bleeding is not due to cancer in about two thirds of the cases.
However, bleeding does not always occur and sometimes endometrial
hyperplasia and even neoplasia are detected fortuitously, at sonograms
or hysteroscopic examination. The hyperplastic changes may involve
Early Diagnosis of Endometrial Cancer 151
the endometrium diffusely or regionally as is the case with endometrial polyps.
Endometrial polyps represent focal lesions of the endometrium
and are most often benign. They are composed of endometrial glands,
stroma, and thickened blood vessels in various proportions. While the
glands are often inactive, similar to those seen in the basal endometrial layer, and cystic with benign epithelial lining, hyperplastic and
neoplastic changes can occur in endometrial polyps. They may
represent precancerous lesions. The surgical removal of endometrial
polyps and their histological examination is mandatory. Their development involves a monoclonal proliferation of endometrial stromal
cells.
3
Both glandular and stromal cells in the polyp have to be exam-
ined for possible precursor or overt malignant changes.
Pathology
On gross examination, the endometrial cavity containing hyperplastic
tissue may be thickened to various degrees, uniformly or with polypoid structures protruding into the cavity. In postmenopausal
women, endometrial hyperplasia may also be found in a thin, grossly
atrophic-appearing endometrium. The histologic diagnosis of
endometrial hyperplasia is based on architectural and cytologic criteria classically divided into a three-tier system that was first described
in 1947 by SB Gusberg as adenomatous hyperplasia (mild, moderate,
severe) and then by the WHO in 1994 as simple, complex, and atypical hyperplasia.
1
A recent trend is to classify endometrial hyperplasia
into benign and potentially precancerous (endometrioid and EIN).
The basic question is whether there is a continuity between the hormonally induced exaggerated endometrial hyperplasia and its neoplastic transformation into an independently growing tumor tissue.
The continuous unopposed (by progesterone) estrogenic stimulation
may elicit continuous endometrial proliferation resulting in simple,
cystic, and complex glandular hyperplasia. Simple glandular hyperplasia consists of glandular proliferation at the detriment of the stroma,
thus increasing the proportion between glands and stroma that is normally 1/1. The glands appear crowded and display dilatation often
152 L Deligdisch
forming cystic structures and outpouching into the adjacent stroma
(Fig. 1). The epithelial cells lining the glands are tall columnar and
pseudo-stratified. Their nuclei are round to oval, hyperchromatic with
a thickened nuclear membrane, and a variable number of mitoses
which are generally symmetrical, similar to those seen in the normal
proliferation phase. Complex glandular hyperplasia represents a more
advanced stage, probably resulting from a more prolonged or more
intense estrogenic stimulation. It is characterized histologically by a
complex glandular pattern with branching, irregular outlines, and papillary infoldings that compress the surrounding stroma, thus increasing
the glandular crowding and the stroma becomes considerably diminished (Fig. 2). Frequently, there is also a breakdown of the stroma and
vascular microthrombosis with hemorrhage. The glandular lining
often is piled up to form a stratified layer. The cells exhibit a variable
amount of mitotic activity, and occasionally undergo squamous metaplasia that may fill the glandular lumen with polygonal immature uniform squamous cells which represent “squamoid morules” (Fig. 3).
Early Diagnosis of Endometrial Cancer 153
Fig. 1 Endometrial simple glandular-cystic hyperplasia in a 51 years old perimenopausal woman with persistent estrogen effect. Hematoxylin/eosin, orginal
magnification 100×.
The most important diagnostic issue for endometrial hyperplasia
is the identification of atypical lesions. Histologically, atypia consists
of architectural and cytologic changes bearing the significance of a
certain degree of “commitment” to progress towards malignancy.
The reversibility of atypical hyperplasia after progesterone therapy, as
opposed to simple, cystic, and complex glandular hyperplasia, due to
the down regulation of estrogen receptors by progestins,
2
is questionable. The data in the literature mention a 25%–40% progression
to adenocarcinoma of lesions diagnosed as atypical complex glandular
hyperplasia.
1
Endometrial atypical glandular hyperplasia consists of marked
glandular crowding, with a back-to-back configuration and nuclear
changes involving an increased nuclear-cytoplasmic ratio, coarse
chromatin clumping, prominent nucleoli, and an irregular thickened
154 L Deligdisch
Fig. 2 Endometrial complex glandular hyperplasia resulting from prolonged estrogen
effect. Glands are crowded with complex lumina, stroma is diminished. Hematoxylin/
eosin, orginal magnification 100×.
nuclear membrane (Fig. 4). Stratification and mitotic activity are variable. Glandular crowding with stromal breakdown, in the absence of
cytologic changes, are not diagnostic for severe/atypical hyperplasia.
Recently, a new classification of endometrial hyperplasias into
benign endometrioid and endometrial intraepithelial neoplasia (EIN)
has been proposed.
3
EIN was defined as a separate category of monoclonal premalignant lesion, different from the benign endometrial
hyperplasia. EIN was assumed to infer a 45-fold higher long term cancer risk as compared to the polyclonal benign hyperplasia which is
associated with prolonged estrogen effect and has a two- to ten-fold
increased risk for endometrial carcinoma.
3,4
The two lesions often
coexist, with EIN lesions displaying clearly atypical nuclear characteristics. They represent localized monoclonal outgrowths of mutated
endometrial cells with an atypical architectural and cytologic configuration to be recognized when compared with the background source
polyclonal field.
3
Molecular biology studies identified a frequent
(63%) inactivation of the PTEN tumor suppressor gene
5
suggesting a
Early Diagnosis of Endometrial Cancer 155
Fig. 3 Endometrial complex glandular hyperplasia with squamoid morules.
Hematoxylin/eosin, orginal magnification 40×.
premalignant potential of this lesion. The hormonal risk factors are
the same for EIN and benign hyperplasia, with estrogens acting as
promoter and progestins as protectors. High levels of nuclear estrogen and progesterone receptors are found in EIN lesions, and unopposed estrogens may act as positive selection factors for previously
mutated cells allowing further clonal expansion. Genetically intact
endometrial glands shut down the PTEN expression on progesterone
exposure.
3
It should be mentioned that the histological appearance at
the diagnosis of an endometrial biopsy from a patient with EIN
treated with progesterone may be heavily modified and difficult to
interpret due to the non-proliferating appearance of the glands, showing secretory changes and the stromal decidual reaction. Hyperplastic
lesions may persist, however, in a deceptively quiescent appearing
endometrium.
Associated histologic changes often noted in endometrial hyperplasia of various degrees of severity are metaplasias (changes into
156 L Deligdisch
Fig. 4 Endometrial atypical glandular hyperplasia (EIN). The endometrial gland is
partially filled with atypical epithelial cells, piled up, with loss of polarity, displaying
increased nuclear-cytoplasmic ratio and prominent nucleoli. Hematoxylin/eosin,
orginal magnification 400×.
Early Diagnosis of Endometrial Cancer 157
different mature tissue patterns), most commonly tubal and occasionally eosinophilic, clear cell or mucinous metaplasias, all of
which are probably related to estrogenic and progesterone stimulation. In the stroma, there may be aggregates of foamy histiocytes
with cytoplasmic vacuoles containing lipid droplets that are actually
deposits of steroids reflecting a local deposit of excessive steroid hormones. These “foamy” histiocytes are seen more often in advanced
degrees of endometrial hyperplasia and in endometrial carcinoma.
Neither the metaplastic epithelial changes nor the stromal foam cell
reaction bear a prognostic significance in terms of precancerous
change.
A very different type of endometrial clearly precancerous lesion is
the endometrial intraepithelial carcinoma (EIC), characterized by
markedly atypical epithelial cells lining the surface and glands, without apparent stromal invasion of a usually atrophic endometrium.
Papillary structures may protrude from the surface or into the glands
(Figs. 5–7). The atypical epithelial cells display enlarged irregular
nuclei with a granular and vesicular chromatin pattern and enlarged
eosinophilic or amphophilic nucleoli. EIC can be seen in endometrial
polyps and has a different immunoreactivity than endometrial hyperplasia, including EIN. In EIC, there is an immunohistochemical overexpression of p53 protein (Figs. 7 and 8) and a loss of heterozygozity
for chromosome 17p. EIC is also encountered in a different clinical
setting. Being relatively independent from hormonal influences, it is
considered as a precursor of endometrial serous adenocarcinoma, a
non-endometrioid variant of endometrial carcinoma which also
expresses immunoreactivity for p53 mutation proteins.
The natural history of EIC is that of a more aggressive lesion, being
a precursor of a non-endometrioid uterine cancer (uterine serous papillary carcinoma) similar in many ways to the ovarian serous carcinoma
with a proclivity to extend to the peritoneal cavity and pelvic organs.
CLASSIFICATION OF ENDOMETRIAL CARCINOMA
Endometrial carcinomas (EC) are classified into two major groups
based on histopathologic, pathogenetic, and clinical characteristics: