The New England Journal o f Me d i c i n e
Review Article
Medical Progress
E NDOMETRIAL C ARCINOMA
PETER G. ROSE, M.D.
U
TERINE cancer is the fourth most frequent
cancer in women, with an estimated 34,000
cases and 6000 deaths in the United States
in 1996.1 It is the most curable of the 10 most com-
mon cancers in women and the most frequent and
curable of the gynecologic cancers. Ninety-seven per-
cent of all cancers of the uterus arise from the glands
of the endometrium and are known as endometrial
carcinomas. The remaining 3 percent of uterine can-
cers are sarcomas, which are not discussed here. Nu-
merous changes in the pathological description of
endometrial cancer, identification of prognostic vari-
ables, staging, and treatment have occurred in the
past 15 years. This article will review the current
understanding of the epidemiology, diagnosis, prog-
nostic factors, and initial treatment of endometrial
carcinoma.
EPIDEMIOLOGY AND PATHOGENESIS
The median age of patients at the diagnosis of en-
dometrial carcinoma is 63 years.2 The incidence of
endometrial carcinoma is highly dependent on age;
there are 12 cases per 100,000 women at 40 years
of age and 84 per 100,000 at 60.3 Seventy-five per-
cent of women with endometrial carcinoma are post-
menopausal.4 Approximately 50 percent of endome-
trial carcinomas occur in women with particular risk
factors for the disease.5
Excessive estrogen is associated with most of the
risk factors that have been linked to endometrial car-
cinoma6 (Table 1). Excessive estrogen produces con-
tinued stimulation of the endometrium, which can
result in endometrial hyperplasia. Women with hy-
perplasia but without atypical cytologic findings
From the Division of Gynecologic Oncology, Department of Reproduc-
tive Biology, University Hospitals of Cleveland, and the Ireland Cancer
Center, Case Western Reserve University, Cleveland. Address reprint re-
quests to Dr. Rose at the Division of Gynecologic Oncology, Department
of Reproductive Biology, University Hospitals of Cleveland, 11100 Euclid
Ave., Cleveland, OH 44107.
1996, Massachusetts Medical Society.
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classified as simple or complex hyperplasia on the ba-
sis of cellular architecture have a low risk of uter-
ine cancer. However, women who have hyperplasia
with atypical cytologic features have a 23 percent risk
of endometrial carcinoma over the next decade.7
Obesity is a risk factor for endometrial carcinoma.
The development of cancer in obese women is be-
lieved to be mediated by endogenous estrogen,
through the conversion of androstenedione to es-
trone by aromatase in adipose tissue.8 The level of
risk is related to the degree of obesity and is in-
creased 10-fold for women who are more than 23 kg
(50 lb) overweight. Early menarche and late meno-
pause are both risk factors for endometrial carcino-
ma, apparently since they lengthen the exposure of
the endometrium to estrogen. Both granulosa-cell
and theca-cell tumors of the ovary produce estro-
gen, and 5 to 15 percent of patients with such tumors
have a synchronous endometrial carcinoma.9
Twenty-five percent of women with endometrial
cancer are premenopausal, and 5 percent are less
than 40 years of age.4,10 The majority of young wom-
en with endometrial carcinoma are obese or have
high levels of unopposed endogenous estrogen be-
cause they have chronic anovulation, such as those
with polycystic ovary disease. Although serum estro-
gen and progesterone concentrations increase dur-
ing pregnancy, progesterone is the predominant hor-
mone of pregnancy. Pregnancy confers protection
from endometrial carcinoma by interrupting the con-
tinued stimulation of the endometrium by estrogen.
Nulliparity is thus a risk factor for endometrial car-
cinoma.
Unopposed exogenous estrogen administered for
the treatment of menopausal symptoms, as was pop-
ular in the late 1960s and 1970s, has been recognized
as a pathogenic factor in endometrial carcinoma, as-
sociated with an eightfold increase in incidence.11,12
This practice resulted in an increase in the incidence
of endometrial carcinoma in the United States to
39,000 cases per year. Since the practice of prescrib-
ing unopposed estrogen has been discontinued and
combined estrogenprogesterone preparations have
been adopted, the incidence of endometrial cancer
has decreased. However, endometrial cancers con-
tinue to occur in women treated with combined
hormone-replacement regimens that include less
than the recommended 12 days of progesterone
monthly.13,14 A worldwide increase in the incidence
of endometrial cancer has been reported, even in
countries where unopposed estrogen is not pre-
scribed; this increase has been attributed in part to
increasing longevity in women.
 M E D I CA L P RO G R E S S
TABLE 1. ESTIMATED RISK RATIOS
FOR ENDOMETRIAL CANCER,
ACCORDING TO SELECTED RISK FACTORS.*
RISK FACTOR RISK RATIO
Overweight
923 kg (2050 lb) 3.0
23 kg (50 lb) 10.0
No children (vs. 1 child) 2.0
No children (vs. 5 children) 5.0
Late menopause (age, 52 yr or later 2.4
vs. 49 yr)
Diabetes mellitus 2.7
Unopposed estrogen therapy 6.0
Tamoxifen therapy 2.2
Use of sequential oral contraceptives 7.0
Use of combination oral contraceptives 0.5
*Except where otherwise specified, risk ratios are
calculated as the risk of endometrial cancer among
women with the factor in question as compared with
women without the factor. Adapted from Dubeau,6
with the permission of the publisher.
Among women 50 to 59 years of age.
Tamoxifen is a synthetic antiestrogen (estrogen
antagonist) that is used in the treatment of breast
cancer. In addition, tamoxifen has been shown to
have estrogenic (agonist) effects on the endometri-
um and to increase the risk of endometrial carcino-
ma. The association between tamoxifen and endo-
metrial cancer was first recognized in 1985, when
endometrial carcinoma developed in three women
with breast cancer after only 7 to 14 months of ther-
apy.15 Since women with breast cancer have a relative
risk of 1.4 for endometrial cancer, the meaning of
this finding was uncertain.16 However, in a large,
randomized trial comparing adjuvant therapy with
tamoxifen (at a dose of 40 mg per day) with no
adjuvant therapy in women with breast cancer, For-
nander et al. reported a relative risk of 6.4 for en-
dometrial cancer in the tamoxifen group after four
years of follow-up.17 More recently, analysis of the
trial conducted by the National Surgical Adjuvant
Breast and Bowel Project, in which tamoxifen was
given at a dose of 20 mg per day, found a relative
risk of 7.5 for endometrial cancer among women
given tamoxifen as compared with women given pla-
cebo.18 The relative risk of endometrial cancer was
lower (2.2) when the tamoxifen group was com-
pared with historical controls in data from the Sur-
veillance, Epidemiology and End Results Program.
A third trial in which tamoxifen was administered at
a dose of 30 mg per day reported a relative risk of
3.3 for endometrial cancer.19 The distribution of dis-
ease stages and grades was similar to that among
women who did not receive tamoxifen.18
Progesterone is the dominant component of to-
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days oral contraceptive agents, which confer pro-
tection from endometrial cancer. A 1983 study re-
ported a relative risk of 0.5 for the disease among
women who had taken an oral contraceptive agent
for at least 12 months.20 Protection persisted for at
least 10 years after the oral contraceptive was discon-
tinued. These agents differ from the sequential con-
traceptive agents available before 1976, in which es-
trogen was dominant and which were associated
with an increased risk of endometrial carcinoma.
Environmental Factors
Since the worldwide incidence of endometrial car-
cinoma correlates with estimates of per capita fat
consumption,21 many have scrutinized the role of diet
in causing this disease. Japanese immigrants to the
United States have an incidence of endometrial car-
cinoma twice as high as that of Japanese women
who did not emigrate, whereas their risk of cervi-
cal and gastric cancer is lower.22 Cigarette smoking
decreases the risk of endometrial carcinoma by in-
activating estrogen through hydroxylation at the
2-alpha position.23
Familial and Genetic Factors
Endometrial cancer is the most common extraco-
lonic cancer in women with the hereditary nonpoly-
posis colorectal cancer syndrome, also known as the
Lynch syndrome II.24,25 This syndrome of right-sid-
ed colon cancers is also associated with breast and
ovarian cancer and has recently been linked to four
genetic alterations. In families affected by this syn-
drome, endometrial cancer occurs in 4 to 11 percent
of women at a median age of 46 years, which is 15
to 20 years younger than the median age at diagno-
sis in the general population.24,25
Diagnosis and Screening
Endometrial carcinoma is usually diagnosed in its
early stages because most women quickly report
postmenopausal vaginal bleeding to their physicians.
Any postmenopausal bleeding or spotting is suspi-
cious and should be evaluated. The likelihood that
endometrial cancer is the cause of postmenopausal
bleeding depends on the womans age; the probabil-
ity is 9 percent for women in their 50s, 16 percent
for those in their 60s, 28 percent for those in their
70s, and 60 percent for those in their 80s.26 Initial
evaluation in the physicians office should include a
pelvic examination, Papanicolaou smear, and endo-
metrial curettage. To evaluate possible cervical ex-
tension and the possibility of a primary endocervical
adenocarcinoma, it is preferable to perform both en-
docervical and endometrial sampling. Endometrial-
sampling devices currently available for office use are
very accurate in diagnosing endometrial carcinoma
if endometrial tissue is obtained. In cases in which
endometrial tissue is not actually obtained on en-
Vo l u m e 3 3 5 Nu m b e r 9  641
 The New England Journal o f Me d i c i n e
dometrial sampling, dilation and curettage should
be performed in the operating room.27 It is in this
group of women that additional testing with ultra-
sonography or hysteroscopy may provide useful in-
formation.
The use of transvaginal ultrasonography to evalu-
ate patients with postmenopausal bleeding has be-
come increasingly popular in the past decade.28,29
Transvaginal ultrasound transducers allow better res-
olution and more accurate measurement of the
thickness of the endometrium than abdominal trans-
ducers. The thickness of normal and abnormal en-
dometrium varies; mean (SD) thickness has been
measured as 3.41.2 mm in women with atrophic
endometrium, 9.72.5 mm in women with hyper-
plasia, and 18.26.2 mm in those with endometrial
cancer.29 With a cutoff value of 5 mm or more
for abnormal endometrial thickness, few endometri-
al cancers should be missed. In a large multi-institu-
tional study of 1168 women, all 114 women with en-
dometrial cancer and 95 percent of the 112 women
with endometrial hyperplasia had an endometrial
thickness of 5 mm or more.30 Forty-five percent of
the women studied had an endometrium measuring
less than 5 mm. The specificity of endometrial thick-
ness for the diagnosis of endometrial cancer increas-
es at cutoff points of 10 mm or 15 mm, but sensi-
tivity decreases.
The 5-mm cutoff may not hold for women of
Asian descent, for whom a recent study suggested
that a 3-mm cutoff should be used.31 Moreover, in
most studies to date, a limited number of women
have been receiving hormone-replacement therapy,
which alters the median endometrial thickness. Ta-
moxifen also increases the thickness of the endo-
metrium. In one study of transvaginal ultrasonogra-
phy in tamoxifen-treated women and controls, the
endometrium was significantly thicker in the treated
women (mean, 10.45.0 mm, as compared with
4.22.7 mm for the controls; P0.001).32 Ultra-
sound demonstration of intrauterine fluid, tradition-
ally considered to be a risk factor for endometrial
cancer, is also better interpreted if the thickness of
the endometrium is taken into consideration. In two
recent studies comparing office biopsy with ultraso-
nography, however, all cases of endometrial cancer
were diagnosed on the basis of the initial biopsy per-
formed in the office.33,34
Inability to sample the endometrium precludes
accurate evaluation for endometrial cancer. In wom-
en with cervical stenosis, ultrasonography can be
used to guide the performance of dilation and curet-
tage.35 In this procedure, which is valuable in pa-
tients with abnormal anatomical features or cervical
stenosis, ultrasonography is used to guide the place-
ment of the uterine sound and curette. Although
routine hysteroscopy for women with postmeno-
pausal bleeding may provide information on benign
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pathological changes in the endometrium, studies
have not shown it to increase the yield in the diag-
nosis of endometrial carcinoma, and it increases the
cost of the initial evaluation.36,37
The role of screening for endometrial cancer has
not been established, and its use is not yet recom-
mended. In a recent study of women receiving hor-
mone-replacement therapy, in which endometrial
biopsy was performed before treatment in 801 asymp-
tomatic perimenopausal and postmenopausal wom-
en, only one well-differentiated carcinoma was diag-
nosed.38 The screening of a high-risk group of 597
women 45 to 69 years of age who had hypertension,
diabetes, or both found no endometrial cancers and
6 women with atypical hyperplasia.39
The value of endometrial biopsy to screen women
receiving tamoxifen therapy is being evaluated in the
Breast Cancer Prevention Trial.40 A recent retrospec-
tive review of tamoxifen-treated women who under-
went dilation and curettage found that only those
with the symptom of vaginal bleeding had uterine
cancer.41
The optimal interval for screening members of
families affected by hereditary nonpolyposis colorec-
tal cancer is not known. In one series, screening with
pelvic examination and endometrial curettage every
three years led to diagnosis in one asymptomatic
woman.42 Some have recommended yearly pelvic ex-
aminations, endometrial biopsy, and pelvic ultraso-
nography beginning at the age of 25.43
Prognostic Factors
Endometrial carcinoma is a heterogeneous disease
with five-year survival rates ranging from 36 percent
to 95 percent for women with disease in clinical
stage I. A variety of factors have been identified that
provide a logical approach to therapy and are predic-
tive of outcome.
In most women with uterine cancer, surgery is the
initial treatment. The prognosis depends so strongly
on the surgical and pathological findings that in
1988 the International Federation of Gynecology
and Obstetrics (FIGO) adopted a surgical staging
system to replace the clinical staging system previ-
ously used (Table 2). In a population-based study of
women with uterine cancer, 81 percent had surgical
stage I; 11 percent had stage II; 6 percent had stage
III; and 2 percent had stage IV.44 The five-year sur-
vival rates for women with disease at these stages were
83 percent, 73 percent, 52 percent, and 27 percent,
respectively.44
The endometrial-curettage specimen can provide
important information regarding the histologic type
and grade of the tumor. Slightly more than a decade
ago, certain histologic subtypes of endometrial car-
cinoma were recognized to have markedly different
prognoses. Christopherson et al. described adeno-
carcinoma, adenoacanthoma, adenosquamous carci-
 M E D I CA L P RO G R E S S

TABLE 2. 1988 SYSTEM FOR SURGICAL STAGING OF CARCINOMA OF THE UTERUS.

STAGE AND GRADE FEATURES

Stage IA; grade 1, 2, or 3 Tumor limited to endometrium

Stage IB; grade 1, 2, or 3
Stage IC; grade 1, 2, or 3
Stage IIA; grade 1, 2, or 3
Stage IIB; grade 1, 2, or 3
Stage IIIA; grade 1, 2, or 3
Stage IIIB; grade 1, 2, or 3
Stage IIIC; grade 1, 2, or 3
Stage IVA; grade 1, 2, or 3
Stage IVB
Invasion of less than half the myometrium
Invasion of more than half the myometrium
Endocervical glandular involvement only
Cervical stromal invasion
Tumor invading serosa or adnexa, or malignant peritoneal cytology
Vaginal metastasis
Metastasis to pelvic or para-aortic lymph nodes
Tumor invasion of the bladder or bowel mucosa
Distant metastasis including intraabdominal or inguinal lymph nodes

noma, clear-cell carcinoma, and papillary serous car-
cinoma, which occurred in 60 percent, 22 percent,
7 percent, 6 percent, and 5 percent of the cases, and
found five-year survival rates of 80 percent, 88 per-
cent, 53 percent, 44 percent, and 68 percent, re-
spectively, for stage I disease.45,46 More recent nomen-
clature has replaced the term adenoacanthoma with
adenocarcinoma with squamous metaplasia and
adenosquamous carcinoma with adenocarcinoma
with squamous differentiation.
The presence of squamous metaplasia or differen-
tiation is not an independent prognostic factor when
corrected for tumor grade.47 Therefore, for clinical
purposes, only the following subtypes of endometri-
al carcinoma need to be recognized: endometrioid
adenocarcinoma, papillary serous carcinoma, and
clear-cell carcinoma (Fig. 1). Papillary serous carcino-
mas are extremely malignant; in recent series, extra-
uterine metastases have been found in up to 72 per-
cent of women; the five-year survival rate is 36 to 40
percent for stage I and II disease, and survival five
years after the diagnosis of stage III and IV disease
is rare.48-50 Women with papillary serous, clear-cell,
or adenocarcinoma with squamous differentiation
have an older median age than women with en-
dometrioid adenocarcinoma.2
The grade is a classification based on tumor ar-
chitecture and reflects the amount of nongland-
forming tumor. Grades 1, 2, and 3 indicate solid
growth patterns in 5 percent or less, 6 to 50 per-
cent, and more than 50 percent of the tumor. In
one population-based study, the frequencies of
FIGO grades 1, 2, and 3 were 30 percent, 42 per-
cent, and 27 percent, respectively.44 The grade of
the carcinoma is highly predictive of the extent
of disease, with pelvic nodal metastasis present in
3 percent, 9 percent, and 18 percent and para-aor-
tic nodal metastasis present in 2 percent, 5 percent,
and 11 percent of grade 1, grade 2, and grade 3 tu-
mors clinically limited to the uterus, respectively.51
The grade of the tumor alone is an important pre-
dictor of survival; the five-year survival rate is 87
percent for women with grade 1 tumors, 75 percent
for those with grade 2 tumors, and 58 percent for
those with grade 3 tumors.44
The association of certain pathological features in
the hysterectomy specimen with pelvic nodal metas-
tasis was reported by Lewis et al. in 1970.52 The Gy-
necologic Oncology Group studied 621 women with
disease at clinical stage I who underwent a standard
surgical staging operation and determined the fre-
quency of pelvic and para-aortic nodal metastasis ac-
cording to the tumor grade and depth of myometrial
invasion (Table 3).51 The presence of unexpected cer-
vical invasion or adnexal involvement and certain his-
tologic types have also been identified as risk factors
for pelvic and para-aortic nodal metastasis.
The presence of malignant peritoneal cytology has
been incorporated into the current surgical staging
system as stage IIIA disease. Malignant peritoneal
cytology is found in 12 to 20 percent of women
with endometrial carcinoma.51,53 Before the incorpo-
ration of this variable into the staging system, stud-
ies had demonstrated that the frequency of malig-
nant peritoneal cytology was 17 percent in women
with disease at clinical stage I, 19 percent at stage II,
68 percent at stage III, and 85 percent at stage IV.
Although the presence of malignant peritoneal cy-
tology was related to pathological features indicat-
ing a poor prognosis, it remained an independent
risk factor for recurrence in the Gynecologic Oncol-
ogy Groups study.51 In other series of surgically
treated women with early-stage disease, however, the
presence of malignant peritoneal cytologic features
has not been prognostic.54,55 In one series of women
with stage IIIA disease, the women were classified
according to whether they had adnexal or uterine se-
rosal involvement, on the one hand, or positive cy-
tologic features alone, on the other.56 Five-year rates
of disease-free and overall survival were significantly

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 The New England Journal o f Me d i c i n e

A B C

Figure 1. The Histologic Subtypes of Endometrial Carcinoma.

Panel A shows endometrioid adenocarcinoma, Panel B papillary serous carcinoma, and Panel C clear-cell carcinoma.

different in these two groups (overall survival, 27
percent and 80 percent, respectively).
Invasion of the vascular space in the hysterectomy
specimen is an adverse prognostic factor related to
the depth of invasion and to tumor differentiation.57
In the Gynecologic Oncology Group study, invasion
of the lymph vascular space was second only to para-
aortic nodal metastasis as a negative prognostic fac-
tor and was associated with a 35 percent rate of re-
currence.58
Although this factor was not evaluated in the Gyn-
ecologic Oncology Groups data, tumor size also ap-
pears to be important; in one study, cancer recurred
in 4 percent of women with tumors 2 cm or less in
diameter, 15 percent of those with tumors greater
than 2 cm, and 35 percent of those with tumors in-
volving the entire endometrium.59
Two groups of women with endometrial carcino-
ma who have distinctly different prognoses have been
described (Table 4).60 Women with type I endome-
trial cancer frequently have estrogen-related risk fac-
tors for the disease, including obesity, nulliparity,
and unopposed estrogen therapy. The prognosis for
such women with early endometrial cancers is excel-
lent. The inherent problem with screening for en-
dometrial cancer on the basis of these risk factors is
that it identifies a low-risk group with an excellent
prognosis. Women with type II endometrial cancer
have adverse histologic features, including poorly
differentiated tumors, papillary serous and clear-cell
tumors, deep myometrial invasion, and extrauterine
disease. Risk factors for type II endometrial cancer,
which has a substantially poorer prognosis, have not
been identified.
Clinical Characteristics
Advanced age adversely affects survival in en-
dometrial carcinoma.3 Younger women tend to have
better-differentiated lesions, but some studies sug-
gest that after adjustment for tumor grade, age is not
an independent risk factor. However, some studies
have reported that disease is more advanced at diag-
nosis in premenopausal women because of delay by
both the women and physicians in evaluating symp-
toms.61
The age-adjusted incidence of endometrial carci-
noma among white women is 23.0 per 100,000, as
compared with 13.9 per 100,000 among black wom-
en.2 Survival among black women with endometrial
carcinoma is significantly worse than among white
women (relative risk of death, 2.7).62 Delay in seek-
ing treatment does not explain this discrepancy.63
Poorly differentiated endometrial carcinoma is more
common among black women than white women
(odds ratio, 2.8 to 8.3).64,65 Other pathological fea-
tures associated with a poor prognosis including
deep myometrial invasion, nodal metastases, and
malignant peritoneal cytology are significantly

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 M E D I CA L P RO G R E S S

TABLE 3. TUMOR GRADE, DEPTH OF MYOMETRIAL INVASION,

AND PELVIC ORPARA-AORTIC NODAL METASTASIS IN PATIENTS WITH UTERINE CANCER.*

GRADE 1 GRADE 2 GRADE 3 GRADE 1 GRADE 2 GRADE 3

DEPTH OF INVASION (N180) (N288) (N153) (N180) (N288) (N153)

no. (%) with pelvic nodal metastasis no. (%) with para-aortic nodal metastasis

Endometrium only (n86) 0 1 (3) 0 0 1 (3) 0

Inner (n281) 3 (3) 7 (5) 5 (9) 1 (1) 5 (4) 2 (4)
Middle (n115) 0 6 (9) 1 (4) 1 (5) 0 0
Deep (n139) 2 (11) 11 (19) 22 (34) 1 (6) 8 (14) 15 (23)

*Percentages represent the proportion of women who had metastases in each subgroup defined by both tumor grade
and depth of invasion. Data are from Creasman et al.51

more common in black women.66 Postmenopausal epidermal growth factor receptors, DNA ploidy was
estrogen use is more common and the duration of the only nonclinical factor that remained statistically
estrogen use is longer among white than among black significant.75 A similar analysis found p53 to be the
women with endometrial carcinoma.64 strongest predictor of survival.76 The implications of
Prognostic scoring systems using both clinical and these biologic markers for treatment are not yet
pathological variables have been described.55,67 clear.
Biologic Markers Treatment
The most extensively studied biologic markers in Surgery is the primary treatment for 92 to 96 per-
endometrial carcinoma are estrogen and progester- cent of women with endometrial carcinoma. Preop-
one receptors. It has been shown that high levels of erative evaluation should include a complete medical
estrogen and progesterone receptors directly corre- history and physical examination, pelvic and rectal
late with better tumor differentiation, less myome- examination with stool guaiac test, chest radiogra-
trial invasion, and a lower incidence of nodal metas- phy, complete blood count, and blood-chemistry
tases and that they independently predict better tests, including tests of liver function. Routine ab-
survival.68,69 dominal and pelvic imaging has an extremely low
Chromosomal measures of tumor activity, includ- yield and is not recommended.77 Ultrasonography
ing DNA aneuploidy, an increase in the S-phase and magnetic resonance imaging have been advocat-
fraction, and the DNA proliferative index, have been ed for evaluating the depth of myometrial invasion
associated with poor survival among women with and may be useful for gynecologists who do not per-
endometrial cancer; these factors are independent of form nodal dissection to help identify women who
clinicopathological features.70 may benefit from referral to a gynecologic oncolo-
Overexpression of the human neu gene, known as gist.78 Routine colonoscopy has been advocated in
HER-2/neu, has been shown to be an important view of epidemiologic risk factors common to both
prognostic factor in breast and ovarian cancer. Ten colon and uterine cancers, but is not recommended
percent of endometrial cancers express HER-2/neu.71
Expression of this gene has been identified in 27
percent of women with metastatic disease, as com-
pared with 4 percent of those with disease limited to
the uterus.71 An inverse relation between HER-2/neu TABLE 4. CHARACTERISTICS OF WOMEN WITH TWO
and progesterone-receptor expression has been dem- PATHOGENETIC TYPES OF ENDOMETRIAL CARCINOMA.
onstrated.72
Mutations of the p53 tumor-suppressor gene have CHARACTERISTIC TYPE I TYPE II
been identified in some endometrial cancers and are
Estrogen use Present Absent
associated with advanced stage, poor tumor differen-
Obesity Present Absent
tiation, the absence of progesterone receptors, se- Tumor
rous papillary carcinoma, and a poor prognosis.73,74 Grade Grade 1 or 2 Grade 3
In a multivariate analysis that included clinical and Depth of invasion Superficial Deep
Nodal metastasis Infrequent Frequent
pathological findings as well as DNA ploidy, estro-
Stage Low High
gen-receptor status, progesterone-receptor status, Prognosis Excellent Poor
p53 and HER-2/neu expression, and the level of

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 The New England Journal of Me d i c i n e
TABLE 5. CLASSIFICATION OF THE RISK OF RECURRENCE
IN WOMEN WITH ENDOMETRIAL CANCER.
LOW RISK
Stage I, grade 1 or 2, nonserous and
nonclear-cell adenocarcinoma
with invasion of the inner third
or less of the myometrium
unless the stool is guaiac-positive or the woman has
symptoms. The concentration of CA-125, a tumor
marker originally described in nonmucinous ovarian
cancer, is elevated in the serum of some women with
endometrial cancer.79 High preoperative CA-125
values have been used to predict the presence of a
more advanced disease stage than is clinically appar-
ent. If CA-125 concentrations are elevated at diag-
nosis, they may also be useful in detecting recur-
rence.80,81
At the time of surgery, peritoneal cytologic sam-
pling, abdominal exploration, palpation and biopsy
of any suspicious lymph nodes or lesions, and extra-
fascial abdominal hysterectomy and bilateral salpin-
go-oophorectomy are performed. The addition of
pelvic lymphadenectomy increased survival in one
study.82 However, since the indications for radiation
therapy were not clearly defined in that study, this
finding requires confirmation. Pelvic and para-aortic
lymphadenectomy is appropriate when the specimen
obtained on dilation and curettage or hysterectomy
has pathological features indicating a poor progno-
sis, such as a grade 3 serous or clear-cell tumor, mid-
dle or deep myometrial invasion, or extension of tu-
mor to the cervix or adnexa.77
After its removal, the uterus is opened and frozen
sections are examined from the areas of deepest tu-
mor invasion (selected on gross examination); sec-
tions from the endocervix should also be examined
when the results of prior endocervical curettage are
positive or when indicated by gross pathological
findings. The overall accuracy of the examination of
frozen sections for identifying high-risk pathological
factors is 94 percent, as compared with a sensitivity
of gross inspection alone of 71 percent.83,84 Infracol-
ic omentectomy has also been performed for serous
papillary tumors of the endometrium.50 Vaginal hys-
terectomy has been used for the management of en-
dometrial cancer, with survival rates similar to those
among women undergoing abdominal hysterecto-
my.85 Laparoscopically assisted vaginal hysterectomy
and laparoscopic nodal dissection have also been re-
ported in the treatment of endometrial cancer.86,87
On the basis of pathological factors, a woman may
be classified as having a low, intermediate, or high
risk of recurrence, and adjuvant therapy should be
646  Au g u s t 2 9 , 1 9 9 6
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INTERMEDIATE RISK HIGH RISK
Stage I, grade 1, 2, or 3, nonserous Stage II, III, or IV
and nonclear-cell adenocarcinoma disease or serous
with invasion of the middle or deep or clear-cell
third of the myometrium carcinoma
considered in this context (Table 5). After primary
surgical treatment, the extent of disease can be de-
termined and the field for adjuvant radiation therapy
can be more appropriately tailored to treat the pel-
vis, the pelvis and para-aortic region, or the whole
abdomen (Table 6). Although pelvic radiation ther-
apy is widely used, its effect on survival is not estab-
lished; only one randomized study has been report-
ed.88 Aalders et al. randomly assigned 540 women
who had undergone hysterectomy and postoperative
vaginal radiation therapy to additional pelvic irradi-
ation or observation.88 Although pelvic radiation
therapy improved local control of disease, survival
did not differ in the two treatment groups. Whether
the addition of pelvic irradiation is appropriate in
the absence of extrauterine metastases in women
who have undergone complete surgical staging awaits
the results of a recently completed randomized
study of the Gynecologic Oncology Group. Because
of the estrogen dependence of early endometrial
carcinoma, the use of adjuvant progestational thera-
py has been studied in five randomized trials; no
benefit has been demonstrated.89
Preoperative radiation therapy followed by hyster-
ectomy has become less popular because it may
overtreat women who have less extensive disease, it
undertreats those with more extensive disease, and it
makes the pathological evaluation of the uterus more
difficult.
Primary radiation therapy is reserved for women
for whom the risks of surgery are high, including
very elderly women and those with multiple medical
problems, who together make up 4 to 9 percent of
women with endometrial carcinoma.90,91 In this high-
risk group, up to 36 percent die of intercurrent
disease.91 A casecontrol study with matching ac-
cording to clinical stage and tumor grade found no
significant difference in survival between women
treated surgically and those who received primary ra-
diation therapy.91 Improved intraoperative and post-
operative care has made it possible to treat all but a
few women surgically. However, as longevity increas-
es among women, patients with endometrial carci-
noma may be older and may have more severe med-
ical problems; primary radiation therapy should be
considered for such patients.
 M E D I CA L P RO G R E S S
TABLE 6. TREATMENT OF HIGH-RISK STAGE I
AND ADVANCED-STAGE ENDOMETRIAL CANCER.
DISEASE STAGE TREATMENT
Stage I, grade 3 Surgical staging
Radiotherapy of the whole pelvis (4550 Gy)
Stage IC or IIA Surgical staging
Radiotherapy of the whole pelvis (4550 Gy)
Stage IIB Surgical staging
Radiotherapy of the whole pelvis (4550 Gy)
Intracavitary radiotherapy
Stage III Surgical staging
Radiotherapy of the whole pelvis (4550 Gy)
Para-aortic radiotherapy (45 Gy) if para-aortic nodes
are positive
Possible pelvic and abdominal radiotherapy
Stage IV Possible pelvic and abdominal radiotherapy
Possible progestin therapy
Possible chemotherapy
Occasionally, women with well-differentiated stage
I endometrial carcinoma have had complete tumor
regression with primary hormonal therapy.92 Some
of these women have gone on to have normal preg-
nancies.93
For women with disseminated disease, systemic
therapy with progestational hormones or cytotoxic
chemotherapy can be considered. Hormone therapy
is preferable, since the toxicity and ease of adminis-
tration of these agents, and the duration of response,
compare favorably with those of cytotoxic chemo-
therapy. Unfortunately, response rates are low, vary-
ing from 10 percent to 34 percent.94 Certain char-
acteristics including well-differentiated tumors, a
long disease-free interval, and positivity for estrogen
and progesterone receptors identify a subgroup
of women who are most likely to respond to hormo-
nal therapy. Kauppila noted responses in 89 percent
of women with progesterone-receptorpositive tu-
mors, as compared with 17 percent of those whose
tumors were negative for progesterone receptors.95
There is no apparent difference in activity among
the numerous progestational agents that have been
used. In contrast to the situation in women with
breast cancer, very-high-dose therapy has not been
associated with a higher rate of response than stand-
ard-dose therapy.96
Cytotoxic chemotherapy is often used for ad-
vanced or recurrent endometrial carcinoma when
hormonal therapy is ineffective. The combination of
doxorubicin, cisplatin, and carboplatin has substan-
tial activity (a response rate of 15 percent or more)
in untreated women.94 In a randomized trial com-
paring doxorubicin alone to doxorubicin plus cis-
platin, the addition of cisplatin significantly im-
proved the response rate (66 percent vs. 35 percent)
and the progression-free interval (6.2 vs. 3.9 months)
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Copyright 1996 Massachusetts Medical Society. All rights reserved.
but not the median survival.97 Recently, the use of
paclitaxel has led to an impressive 35 percent re-
sponse rate in previously untreated women.98 Plans
are being made to incorporate paclitaxel into multi-
agent regimens.
Although adenocarcinoma of the endometrium is
an estrogen-dependent tumor, retrospective studies
of estrogen-replacement therapy after the treatment
of low-risk stage I endometrial carcinoma have found
no apparent increase in the risk of recurrence.99 The
American College of Obstetricians and Gynecolo-
gists recommends that physicians and patients assess
the risk of estrogen-replacement therapy in the con-
text of the risk of recurrent disease.100
Future directions in the management of endome-
trial carcinoma are currently being addressed in nu-
merous randomized clinical trials by the Gynecolog-
ic Oncology Group. A study comparing adjuvant
chemotherapy with pelvic irradiation in patients with
high-risk stage I and stage II tumors is ongoing. An-
other study is currently comparing abdominal irra-
diation with doxorubicin plus cisplatin for stage III
and IV tumors limited to the abdomen with residual
disease less than 2 cm in diameter. A better under-
standing of the molecular biology of endometrial
cancer may provide insights into the variable behav-
ior of this disease.
I am indebted to Drs. Michael Rodriguez and Beth Nelson for
their comments.
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