ENDOMETRIAL CANCER
Carcinoma of the uterine endometrium is the most
common pelvic malignancy in women. The USAand Canada have the highest incidence
rates in the world, whereas developing countries and Japan have inci- dence
rates four to five times lower. Epidemiologic data indicate that there are two
forms of endometrial cancer. One is directly related to estrogen exposure and
is most common in the USA. The other is unre- lated to estrogen and occurs
throughout the world. Estrogen-related type I tumors occur among younger
perimenopausal women and carry a good prognosis. In fact, type I lesions are
potentially preventable through recognition of patient risk, diagnosis of the
precursor lesion (atypical endometrial hyperplasia) and proper treatment.
Non-estrogenrelated type II tumors occur in older postmenopausal women without
a history of estrogen exposure and have a poorer prognosis. The molecular
genetic alterations present in type I and II endometrial carcinomas are
distinct and may help to explain their clinical characteristics.
Cells of the
Müllerian tract can differentiate into a wide range of tissue types. This is
demonstrated by the variety of histologic subtypes seen among the endometrial
cancers. The vast majority are endometrioid adenocarcinomas. Prognosis for
patients with endometrioid adenocarcinoma is determined largely by its degree
of differentiation or histologic grade (well, moderately or poorly
differentiated). In fact, histologic grade is a prognostic factor independent
of stage at diagnosis. Less common histologic subtypes include mucinous
adenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma, squamous cell
carcinoma and a variety of rare mixed and undifferentiated tumors. For all
subtypes other than endometrioid adenocarcinoma, prognosis depends more on
histologic subtype than on histologic grade.
Endometrioid
adenocarcinoma first invades the stroma of the underlying uterine tissue by
destroying the glandular basement membrane. It then invades the myometrium and
cervix. Endometrioid adenocarcinoma typically spreads via the pelvic and
periaortic lymphatic channels rather than hematogenously. Vascular invasion is
usually seen only with high-grade, non-estrogen-dependent lesions.
Treatment of
endometrial cancer usually involves surgical removal of the uterus, fallopian
tubes and ovaries. Patients with deep myometrial invasion or disease outside of
the uterus may be treated postoperatively with radiation, chemotherapy or
progestin-based hormonal therapies. Pretreatment analysis of endometrioid adenocarcinoma
specimens for estrogen and progesterone receptor status may help to direct
postsurgical therapy. There is a good correlation between tumor differentiation
and receptor content. Well-differentiated tumors usually have greater numbers
of estrogen and progesterone receptors. Because receptor content predicts
response to progestin therapy, patients with well- differentiated tumors may be
good candidates for progestin therapy.
The survival
rate for endometrial cancer is relatively good. Overall, survival approaches
70% at both 5 and 10 years. Patients with stage 1 disease, in which the tumor
has not invaded through more than half the myometrial thickness, have a 5-year
survival rate of over 90%. Because of its high prevalence, endometrial cancer
can be considered a neoplasia of high morbidity and relatively low mortality in
developed countries.
Epidemiology Of Endometrial Cancer
Endometrial cancer
is largely a disease of the postmenopausal woman. About 80% of cases diagnosed are
in women aged 50–75 years of age, with peak incidence in those aged 55–70. A
woman entering meno- pause has double the chance of developing endometrial
cancer com- pared with her chance for developing carcinoma of the cervix or the
ovary. The incidence of endometrial cancer varies dramatically from country to
country. This geographic pattern follows that of breast and ovarian cancer,
with the highest rates in industrialized countries. It is exactly the opposite
of patterns observed for cervical cancer.
An
association between estrogen exposure and endometrial cancer has been apparent
for over 50 years. Many of the risk factors listed in Table 43.1 are thought to
increase the risk because of their close association with high estrogen levels,
typically unopposed by progesterone. The single most important and best defined
risk factor for adenocarcinoma of the uterus is obesity. Adipose tissue has
active aromatase enzymes. Adrenal androgens are rapidly converted to estrogens
within the adipose tissue of obese individuals. These newly synthesized
estrogens also have excellent bioavailability because the metabolic changes
associated with obesity inhibit the production of sex hormone-binding globulins
by the liver. Obese individuals may have dramatic elevations in their
circulating bioavailable estrogens and this exposure can cause hyperplastic
growth of the endometrium. Close links exist between the risk of endometrial
cancer, a high-fat diet and gross national product, which suggests that level
of industrial development may affect incidence of endometrial carcinoma by
influencing food consumption. A high-fat diet is also associated with obesity
and type 2 diabetes mellitus. Amount and type of dietary fat influences
estrogen metabolism. For example, diets rich in beef or in fats increase
estrogen reabsorption from the bowel.
White women
are three times more likely to be diagnosed with endometrial cancer than black
women. Again, this is exactly the oppo- site of what is seen for cervical
cancer.
Steroid Hormones And Endometrial
Cancer
As noted
above, the epidemiologic data on endometrial cancer reveal a striking
association between estrogen exposure and cancer development. Interestingly, a direct causal link
can only be inferred at this time. The basis for considering estrogen as an
etiologic factor comes from three sources: (i) the biologic activity of
estrogen and progester- one on the endometrium; (ii) animal and human data on
the effects of diethylstilbestrol (DES) on carcinogenesis; and (iii) the
association of endometrial cancer with endometrial hyperplasia in conjunction
with the association of hyperplasia with prolonged and unopposed estrogen
exposure.
The
strongest attestation to the high sensitivity of the endometrium to ovarian
steroid hormones is the dramatic changes that occur in this tissue during each
menstrual cycle (Chapters 10 and 14). In a normally cycling woman, the
endometrium changes its morphology on a day- to-day basis. In the follicular
phase of the cycle, estrogens stimulate proliferation of the epithelium
covering the endometrial glands and of the underlying stroma. Estrogen induces
production of its own recep- tor and of the progesterone receptor during this
time. Progesterone secreted after ovulation promptly arrests the proliferative
activity in the glands and converts the epithelium to a secretory state. The
stroma responds to progesterone with angiogenesis and functional maturation. If
pregnancy should occur, these changes will prepare the endometrium for
implantation. It is believed that the potent mitogenic effect of estrogen on
the epithelium of the endometrial glands accelerates the spontaneous mutation
rate of predisposing oncogenes and/or tumor suppressor genes. This leads to
neoplastic transformation.
Animal and human
data gathered after developmental exposure to DES add biologic evidence for the
carcinogenic potential of estrogens in the reproductive tract. DES is a
nonsteroidal estrogen agonist that was among the first synthetic estrogens to
be developed. It was admin- istered to over 2 million women between 1940 and
1970 as treatment for threatened miscarriage. In mice, neonatal exposure to DES
produces endometrial cancer in 95% of animals by 18 months of age. In women,
prenatal DES exposure leads to structural abnormalities of the reproductive
tract (Chapter 27) and to clear cell adenocarcinoma of the vagina and cervix.
The carcinogenic action of the DES appears to be mediated in part through
activation of the estrogen receptor. Whether prenatal DES exposure will cause
endometrial cancer in humans will be determined as this cohort of women
continues to be followed through menopause. The molecular genetic mechanism by
which DES lead to clear cell carcinoma and naturally occurring estrogens to
type I endometrial cancer may be similar. Genetic instability of microsatellite
sequences has been demonstrated in both of these tumors.
Molecular biology of endometrial
cancer K-ras
oncogene mutations and microsatellite instability are most common in type I
estrogen-related tumors. Mutations of the PT53 tumor suppressor gene and
overexpression of the ERBB2 oncogene are more frequently observed in
type II non-estrogen-related tumors.
Endometrial Hyperplasia
Endometrial
hyperplasia describes a spectrum of changes in the endometrium. These can range
from slightly disordered patterns that merely exaggerate the changes seen in
the late proliferative stage of the menstrual cycle to irregular,
hyperchromatic lesions that are difficult to distinguish from endometrioid
adenocarcinoma. Nonetheless, noninvasive endometrial hyperplasia can be divided
into two basic types: hyperplasia and atypical hyperplasia. Atypia is
characterized by nuclear enlargement, hyperchromasia or irregularities in
nuclear shape. Hyperplastic lesions can be further subdivided. Simple hyperplasia
describes hyperplastic changes with regular glandular architecture while
complex hyperplasia has irregular glandular architecture (Fig. 43.1a). Of the
four types of endometrial hyperplasias – simple, complex, atypical simple and
atypical complex – only atypical complex hyperplasia poses significant risk for
progression to invasive carcinoma. The progression from hyperplasia is slow and
may take 5 years or more. About 20% of women with complex atypical hyperpla-
sia will develop endometrial adenocarcinoma (Fig. 43.1b). Only 1–2% of those
with the other hyperplastic lesions will progress.
Endometrial
hyperplasia has the same epidemiologic risk factors as endometrial cancer.
Among patients with atypical endometrial hyperplasia, postmenopausal status is
associated with the highest risk of progression to adenocarcinoma (33% over 10
years). Endometrial cancer is rare during the child-bearing years. When it
occurs, it is usually associated with clinical disorders that cause chronic,
unopposed estrogen exposure, including the polycystic ovary syndrome and
chronic anovulation (Chapter 31). Estrogen-producing ovarian tumors, such as
the granulosa–theca cell tumors (Chapter 42), are also associated with the
development of endometrial hyperplasia and adenocarcinoma in premenopausal
women.
Progesterone-based
therapies are used to halt endometrial proliferation and to convert the
endometrium to a secretory state in women with endometrial hyperplasia with low
malignant potential. Treatment can be given cyclically or continuously.
Atypical endometrial hyperplasia is treated surgically (hysterectomy) unless
there is a contraindication to the procedure.
