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C H A P T E R


                                                        5
         Adenocarcinoma of the Uterine Corpus
                 William T. Creasman, MD, and David Scott Miller, MD

                                                 O U T L I N E

 Incidence	                                          141        Tumor Grade	                                     158
                                                                Molecular Indices	                               159
 Epidemiology	                                       141
                                                                Correlation of Multiple Prognostic Factors	      160
 Diagnosis	                                          146
                                                            Treatment	                                           161
    Pathology	                                       149
                                                                Surgical Management of Endometrial Cancer	       161
    Tumor Grade	                                     154
                                                                Radiation Therapy	                               166
 Prognostic Factors	                                 154        Drug Development	                                168
    Stage of Disease: Depth of Invasion, Cervical               Special Circumstances	                           171
       Involvement, Adnexal Involvement, and Nodal              Follow-Up	                                       173
       Metastasis	                                   155




                    INCIDENCE                               of estrogen has been implicated in the apparent increased
                                                            incidence during the 1970s and early 1980s; however,
In the United States, cancer of the uterine corpus is the   Norway and Czechoslovakia report a 50% to 60%
most common malignancy unique to women. It was esti-        increase in endometrial cancer, despite the fact that
mated by the American Cancer Society that uterine           estrogens are rarely prescribed or are not generally avail-
cancer will develop in approximately 42,160 women in        able there. However, the increasing prevalence of over-
2009 in the United States, making it the fourth most        weight and obesity in women, especially in developed
common cancer in women. The increased incidence of          countries, may account for this apparent increase.
carcinoma of the endometrium has been apparent only         Regardless of the reason for the increased number of
during the last three decades. In reviewing the predicted   women with corpus cancer, this malignant neoplasm has
incidence for the 1970s, the American Cancer Society        become an important factor in the care of the female
noted a one and a half-fold increase in the number of       patient.
patients with endometrial cancer; however, there was a
decline in incidence during the late 1980s. In the past
several years, the incidence has remained constant.                            EPIDEMIOLOGY
During the period of increased incidence, predicted
deaths from this malignant neoplasm actually decreased      Endometrial adenocarcinoma occurs during the repro-
slightly. More recently, deaths from uterine cancer have    ductive and menopausal years. The mean age for patients
increased. In 1990 the American Cancer Society esti-        with adenocarcinoma of the uterine corpus is 63 years;
mated 4000 deaths from this cancer, increasing to 7780      most patients are between the ages of 50 and 59 years
in 2009. An estimation of the most common new cancers       (Figure 5-2). Approximately 5% of women will have
and the percentage of female deaths for 2009 in the         adenocarcinoma before the age of 40 years, and 20% to
United States is shown in Figure 5-1. The increased use     25% will be diagnosed before menopause. Bokhman


                                                        141
142	                                                              5.  Adenocarcinoma of the Uterine Corpus



                               Cervix                                                                                     Deaths
                                                                                                                          New cases
                                Ovary


                            Leukemia


                              Uterine


                            Colorectal


                                 Lung


                               Breast

                                         0     20,000    40,000   60,000   80,000 100,000 120,000 140,000 160,000 180,000 200,000 220,000

FIGURE 5-1  Common new cancer cases and deaths in women for 2010 in the United States. (Modified from American Cancer Society. Cancer
Facts and Figures 2010. Atlanta. American Cancer Society, 2010.)




                     3500                                                               clearly defined. Bokhman’s data suggest that patients
                                    Surgical                                            with the first pathogenic type mainly have well-
                     3000           Clinical                                            differentiated or moderately differentiated tumor, super-
                                                                                        ficial invasion of the myometrium, high sensitivity to
                     2500
                                                                                        progestins, and favorable prognosis (85% 5-year sur-
                                                                                        vival in his material). The patients who fall into the
Number of patients




                                                                                        second pathogenic group tend to have poorly differenti-
                     2000
                                                                                        ated tumors, deep myometrial invasion, high frequency
                                                                                        of metastatic disease in the lymph nodes, decreased sen-
                     1500                                                               sitivity to progestin, and poor prognosis (58% 5-year
                                                                                        survival rate).
                     1000                                                                   Multiple risk factors for endometrial cancer have been
                                                                                        identified, and MacMahon divides these into three
                                                                                        categories:
                     500

                                                                                           •	 Variants of normal anatomy or physiology
                       0                                                                   •	 Frank abnormality or disease
                            15-29    30-39     40-49     50-59 60-69   70-79   80+
                                                       Age group                           •	 Exposure to external carcinogens

FIGURE 5-2  Carcinoma of the corpus uteri; patients treated in                             Obesity, nulliparity, and late menopause are variants
1999–2001. Age distribution by mode of staging. (Modified from Creas-                   of normal anatomy or physiology classically associated
man WT et al: Int J Gynecol Obstet 95(1):S105-143, 2006)
                                                                                        with endometrial carcinoma. These three factors are
                                                                                        evaluated in regard to the possible risk of developing
                                                                                        endometrial cancer in Table 5-1. If a patient is nullipa-
                                                                                        rous and obese and reaches menopause at age 52 years
                                                                                        or older, she appears to have a fivefold increase in the
suggested that there are two pathogenic types of endo-                                  risk of endometrial cancer above that of the patient who
metrial cancer. The first type arises in women with                                     does not satisfy these criteria (Table 5-2).
obesity, hyperlipidemia, and signs of hyperestrogenism,                                    The type of obesity in patients with endometrial
such as anovulatory uterine bleeding, infertility, late                                 cancer has been evaluated. In a study from the Univer-
onset of menopause, and hyperplasia of the stroma of                                    sity of South Florida, it was noted that women with
the ovaries and endometrium. The second pathogenic                                      endometrial cancer had greater waist-to-hip circumfer-
type of disease arises in women who have none of these                                  ence ratios, abdomen-to-thigh skin ratios, and suprailiac-
disease states or in whom the disease states are not                                    to-thigh skin ratios than those of matched-control
5.  Adenocarcinoma of the Uterine Corpus	                                       143
TABLE 5-1  Endometrial Cancer Risk Factors                               of consumption of most types of meats, eggs, beans,
                                                                         added fats, and sugar. Conversely, significant protection
Risk Factors                                                   Risk
                                                                         was noted with an elevated intake of most vegetables,
Obesity                                                       2.5-4.5×   fresh fruits, whole grain bread, and pasta. This reflected
Nulliparity                                                              a low risk with increased intake of ascorbic acid and
  Compared with 1 child                                         2×
  Compared with 5 or more children
                                                                         beta-carotene. Of dietary interest is that the intake of
                                                                3×
Late menopause                                                 2.4×      olive oil seemed beneficial in Switzerland but resembled
                                                                         other added fats in the Italian women. It has been previ-
                                                                         ously noted that the amount and type of dietary fat
                                                                         influence estrogen metabolism because estrogen reab-
TABLE 5-2 Multiple Risk Factors                                          sorption from the bowel seems to be increased by diets
                               Risk                                      rich in beef or fats.
                                                                            Diabetes mellitus and hypertension are frequently
Nulliparous                                    Parous
                                                                         associated with endometrial cancer. Elwood and col-
Top 15% in weight

Menopause at 52 years
                           5× more than
                                              Lower two thirds in
                                                 weight
                                               Menopause at <49 years
                                                                         leagues reported a RR of 2.8 associated with a history of
                                                                         diabetes after controlling for age, body weight, and
                                                                         socioeconomic status. High levels of insulin-like growth
                                                                         factor I, coupled with elevated estrogen levels, are
                                                                         thought to have neoplastic potential that accounts for
women. As these ratios increased, the relative risk (RR)                 the observed increased risk of endometrial cancer. High
of endometrial cancer increased. The researchers con-                    blood pressure is prevalent in elderly obese patients but
cluded that upper-body fat localization is a significant                 does not appear to be a significant factor by itself, even
risk factor for endometrial cancer. In a large multicenter               though 25% of patients with endometrial cancer have
case-control study of 403 endometrial cancer cases and                   hypertension or arteriosclerotic heart disease.
297 control cases, Swanson and associates confirmed                         As extensively detailed in Chapter 4, the relationship
and amplified these findings. Women whose weight                         of unopposed estrogen and endometrial cancer is well
exceeded 78 kg had a risk 2.3 times that of women                        documented. Fortunately, the addition of a progestin
weighing less than 58 kg. For women weighing more                        appears to be protective. Adequacy of progesterone is
than 96 kg, the RR increased to 4.3. Upper-body obesity                  important in prevention of endometrial cancer. In a
(waist-to-height ratio) was a risk factor independent of                 study from Sweden, at the end of 5 years excess risk of
body weight. Patients in the highest quartile of both                    endometrial cancer was 6.6 but with combined estrogen
weight and waist-to-thigh circumference had a risk of                    progestin (E + P), RR was 1.6 for 11 to 15 days of proges-
5.8 times. The amount of body fat has been associated                    tin, 2.9 for 10 days of use, and 0.2 if continuous E + P
with decreased circulating levels of both progesterone                   was given. The Million Women study from the United
and sex hormone-binding proteins. There was a strong                     Kingdom has recently reported their findings of endo-
inverse association between sitting height and risk of                   metrial cancer and hormone replacement therapy (HRT).
endometrial cancer. This may be related to sex hormone-                  This study, which first reported on HRT and breast
bound globulin (SHBG), which appears to be depressed                     cancer, has been severely criticized mainly on methodol-
in women with endometrial cancer. The level of SHBG                      ogy factors. They had an average follow-up of 3.4 years,
is progressively depressed with increasing upper-body                    during which 1320 incident endometrial cancers were
fat localization. With lower SHBG, there is a higher                     diagnosed. At time of recruitment 22% of HRT users
endogenous production of non–protein-bound estradiol.                    (total number was 320,953 women) last used continuous
Because endometrial cancer is related to obesity, dietary                combined therapy, 45% last used cyclic combined
habits appear to be important. Data suggest that the                     therapy with progestogen usually added for 10 to 14
levels of estriol, total estrogens, and prolactin were lower             days per month, 19% last used tibolone, and 4% used
and those of SHBG were higher in postmenopausal                          estrogen alone. Compared with nonusers, RR of endo-
women who were vegetarians. In a case-control study,                     metrial cancer was 0.71%, CI 0.56 to 0.90, P = 0.005; 1.05,
Levi and colleagues evaluated dietary factors in 274                     CI 0.91 to 1.22; 1.79, CI 1.43 to 2.25, P <0.001; and 1.45,
patients with endometrial cancer and 572 control sub-                    CI 1.02 to 2.06, P = 0.04, respectively. Of note, the adverse
jects from two areas in Switzerland and northern Italy.                  effects of tibolone and estrogen only were greatest in the
Extensive dietary history was obtained. Their data con-                  nonobese woman and the beneficial effects of combined
firmed the relationship between obesity and endome-                      HRT were greatest in obese women. Although the risk
trial cancer. In relation to diet, they noted an increased               of unopposed estrogen is present, women taking estro-
association with total energy intake. After correction for               gen who develop endometrial cancer appear to have
total energy intake, a risk was present with the frequency               favorable prognostic factors. Several but not all studies
144	                                    5.  Adenocarcinoma of the Uterine Corpus


suggest that risk factors such as multiparity and obesity     differences are unexplained. An analysis of the Gyneco-
are lower in the estrogen users. Stage of disease and         logic Oncology Group (GOG) database evaluated this
histologic grade appear to be lower in estrogen users.        factor in 600 white and 91 black women with clinical
With correction for stage and grade, estrogen users still     stage I or stage II endometrial cancer. A larger number
have less myometrial invasion than nonestrogen users          of the African American women were diagnosed after
do. The poor prognostic subtypes, such as clear cell car-     age 70 years, and they had a higher proportion of papil-
cinoma and adenosquamous cancer, appear less fre-             lary serous (PS) and clear cell histologic types; the black
quently in estrogen users. As a result, survival rates with   women also had more advanced disease, grade, vascular
estrogen-related endometrial cancer are much better           space involvement, depth of invasion, and lymph node
than those of nonestrogen cancers. In fact, some studies      metastases than the white women did. Survival (5-year)
note just as good if not better survival in estrogen users    was 77% for white women and 60% for black women.
than in women with nonestrogen, nonendometrial                Survival difference remained even in high-risk groups
cancers.                                                      such as grade III tumors (59% vs 37%, respectively). The
   Data indicate that the use of combination oral contra-     unadjusted hazard rate was 2.0, which was statistically
ceptives decreases the risk for development of endome-        significant. With adjustment for age, cell type, and extent
trial cancer. The Centers for Disease Control and             of disease, the RR dropped to 1.2. The adjusted risk rate
Prevention evaluated endometrial cancer cases of all          suggests that race is not a significant factor; nevertheless,
women aged 20 to 54 years from eight population-based         race does denote an increased risk for poor prognostic
cancer registries and compared them with control              factors, which clinically may be important.
patients selected at random from the same centers. A             Tamoxifen is used to prevent or treat breast cancer.
comparison of the first 187 cases with 1320 control cases     Tamoxifen was first introduced in clinical trials in the
showed that women who used oral contraceptives at             early 1970s and was approved in 1978 by the U.S. Food
some time had a 0.5 RR of developing endometrial              and Drug Administration (FDA) for treatment of
cancer compared with women who had never used oral            advanced breast carcinoma in postmenopausal woman.
contraceptives. This protection occurred in women who         Tamoxifen, although labeled an antiestrogen, is known
used oral contraceptives for at least 12 months, and pro-     to have estrogenic properties and truly is a weak estro-
tection continued for at least 10 years after oral contra-    gen. Women receiving tamoxifen also appear to have
ceptive use. Protection was most notable for nulliparous      some protection from osteoporosis and heart disease
women. These investigators estimated that about 2000          (decreased lactate dehydrogenase and cholesterol),
cases of endometrial cancer are prevented each year in        much like women receiving estrogen replacement
the United States by past or current use of oral contra-      therapy. Extensive experience with this drug has been
ceptives. Of interest, cigarette smoking appears to           reported. It is estimated that more than 4 million women
decrease the risk for developing endometrial cancer. In       in the United States have taken tamoxifen for almost 8
a population-based case-control study of women aged           million women-years of use. One of its major benefits is
40 to 60 years, Lawrence and associates found a signifi-      that in women taking tamoxifen, there has been a sub-
cant decline in RR of endometrial carcinoma with              stantial decrease in the incidence of a second cancer in
increased smoking (P >0.05). The RR decreased by about        the opposite breast compared with similar women who
30% when one pack of cigarettes was smoked per day            were taking a placebo.
and by another 30% when more than one pack was                   The Early Breast Cancer Trialists Collaborative Group
smoked per day. The effects of smoking did not appear         (EBCTCG) has produced an important meta-analysis of
to vary with menstrual status or exogenous estrogen.          194 randomized trials of adjuvant chemotherapy or
There was a fourfold increase in smoking-related odds         endocrine therapy with at least 15 years of follow-up.
ratio with body weight; the greatest reduction in risk by     The analysis evaluated the effects of adjuvant tamoxifen
smoking was in the heaviest women. However, the esti-         on breast cancer recurrence and survival. It was shown
mated risk increased twelvefold in overweight women           that 5 years of tamoxifen therapy, compared to no adju-
who were nonsmokers and whose primary source of               vant therapy, reduced the 15-year probability of breast
estrogen was peripheral conversion of androgen to             cancer recurrence (from 45% to 33%) and breast cancer
estrogen. Although smoking apparently reduces the risk        mortality (from 35% to 26%). In addition, tamoxifen has
for development of early-stage endometrial cancer, this       been shown to provide a preventive benefit in women
advantage is strongly outweighed by the increased risk        at risk for developing breast cancer.
of lung cancer and other major health hazards associated         There has been a considerable amount of discussion
with cigarette smoking.                                       in the literature in regard to the association of tamoxifen
   Incidence and survival are higher in white women           with endometrial cancer. At least three studies (Fisher
compared with black women. Reasons for these                  and colleagues, Powels and colleagues, and Veronesi
5.  Adenocarcinoma of the Uterine Corpus	                                   145
and colleagues) evaluating the prophylactic use of           the prevention of recurrences and new breast cancer in
tamoxifen in women without breast cancer have reported       comparison to new endometrial cancers were evaluated
an association between tamoxifen use and endometrial         in the NSABP study. The benefits suggest that 121 fewer
cancer. In addition, several cases of endometrial cancer     breast-related events per 1000 women treated with
have been described in women receiving tamoxifen. In         tamoxifen were seen compared with 6.3 endometrial
a prospective, randomized study of the National Surgi-       cancers per 1000 women. Therefore the benefit from
cal Adjuvant Breast and Bowel Project (NSABP), 2843          tamoxifen is apparent.
patients with node-negative estrogen receptor–positive           It was initially suggested that the rate of endometrial
invasive breast cancer were randomly assigned to receive     cancers associated with tamoxifen might be equal to
a placebo or 20 mg/day of tamoxifen. An additional           that associated with unopposed estrogen replacement
1220 tamoxifen-treated patients were registered and          therapy. Because tamoxifen is a weak estrogen, similar
given the drug. The average time in the study was 8          characteristics of endometrial cancer were also implied
years for the randomly assigned patients and 5 years for     (i.e., well-differentiated superficially invasive cancers).
the registered patients. Of the 1419 patients randomly       Barakat and associates reviewed five studies, including
assigned to tamoxifen, 15 developed uterine cancer, of       the study by Magriples, the NSABP, their own data from
which two were sarcomas. One patient randomly                Memorial Sloan-Kettering Hospital, and two studies
assigned to receive tamoxifen did not take the drug and      from overseas. A total of 103 patients were evaluated in
developed endometrial cancer 78 months after random-         regard to histologic features, grade of tumor, Interna-
ization. In the placebo group, two developed endome-         tional Federation of Gynecology and Obstetrics (FIGO)
trial cancer; however, both were receiving tamoxifen at      staging, and deaths from uterine cancer; an increase was
the time of their uterine malignant disease. One patient     not found in poor prognostic histologic findings, tumor
had a breast recurrence and was prescribed tamoxifen,        differentiation, or stage compared with what would be
and the other was given tamoxifen after colon cancer.        expected in a similar group of non–tamoxifen-treated
Two of the patients with endometrial cancer had been         patients with uterine cancer. Jordan, in an evaluation of
taking tamoxifen for only 5 and 8 months before their        the SEER data and of tamoxifen-associated endometrial
diagnosis of uterine disease was made. Five patients         cancer in the literature, reported similar findings.
in the tamoxifen group developed endometrial cancer              It is suggested that all women, irrespective of whether
after the drug had been discontinued for 7 to 73 months.     they are taking tamoxifen, should have yearly gyneco-
In the registered patients who received tamoxifen, eight     logic examinations. The endometrium should be evalu-
uterine tumors (seven endometrial) were subsequently         ated if the patient is symptomatic. We do not currently
diagnosed. Three of these patients had been taking           recommend endometrial sampling or ultrasound evalu-
tamoxifen for less than a year (2 months, 2 months, and      ation of the endometrium just because an individual is
9 months). The authors determined the average annual         taking tamoxifen. This possible concern of tamoxifen
hazard rate of endometrial cancer per 1000 women in          and endometrial cancer may lessen in the near future
their population of patients. This was 0.2 per 1000 in the   because the aromatase inhibitors (AIs) may appear to be
placebo group and 1.6 per 1000 for the randomized            better than tamoxifen in the prevention of recurrent or
tamoxifen-treated patients. In the registered patients       contralateral breast cancer. Several clinical trials have
receiving tamoxifen, the average annual hazard rate was      demonstrated the comparable if not greater efficacy
1.4 per 1000, similar to that of the randomized tamoxifen-   of AIs compared to tamoxifen. Although tamoxifen
treated group. The hazard rate of endometrial cancer in      remains an option for adjuvant therapy for postmeno-
the placebo group was low compared with the Surveil-         pausal women, AIs are thought to be more effective
lance, Epidemiology, and End Results (SEER) data and         in preventing breast cancer recurrence in the first 2
with previous NSABP randomized tamoxifen–placebo             years after surgery. AIs reduce estrogen levels in
studies; these data suggest that the average annual          postmenopausal women by inhibiting or inactivating
hazard rate is 0.7 per 1000.                                 aromatase, the enzyme that synthesize estrogens
   These data, based on a limited number of patients         from circulating androgens. AIs should be avoided in
with endometrial cancer while receiving tamoxifen,           premenopausal women, including those who have expe-
suggest that there may be a RR of 2.3 for development        rienced chemotherapy-induced amenorrhea. Whereas
of endometrial cancer while receiving tamoxifen. This        tamoxifen is a partial agonist, AIs are not agonists and
does not take into account the well-known fact that          are not associated with estrogenic-related thromboem-
women who develop breast cancer are at an increased          bolic events and uterine cancers. The activity of third-
risk for development of endometrial cancer irrespective      generation agents anastrozole, letrozole, and exemestane
of subsequent treatment. The RR of 1.72 to more than         is generally considered comparable. Although AIs
3 has been reported. The risks and benefits of               are associated with a significant risk of osteoporosis,
146	                                    5.  Adenocarcinoma of the Uterine Corpus


they do not increase the risk of gynecologic problems. In     ovaries has been shown to decrease the risk of uterine
one large adjuvant therapy trial (the Anastrozole,            and ovarian cancer in these high-risk patients.
Tamoxifen Alone or in Combination Trial [ATAC]), anas-
trozole was associated with fewer cerebrovascular events
(2.0% vs 2.8%), endometrial cancers (0.2% vs 0.8%)                                 DIAGNOSIS
thromboembolism (2.8% vs 4.5%), hot flashes (41% vs
36%), and vaginal bleeding (5.4% vs 10.2%) compared           Routine screening for uterine adenocarcinoma and its
with tamoxifen. The role of AIs as prophylaxis is             precursors is not recommended. Women receiving HRT
being investigated, but data are lacking at the present       (estrogen and progesterone) do not need endometrial
time.                                                         biopsy before institution of therapy or during replace-
    Although most cases of endometrial cancer are spo-        ment therapy unless abnormal bleeding occurs. Monthly
radic, hereditary endometrial cancer has been identified      withdrawal bleeding after progestin is not considered
in association with hereditary nonpolyposis colon             abnormal bleeding. However, breakthrough bleeding
cancer (HNPCC), also known as Lynch II syndrome.              should be evaluated. The use of continuous estrogen
This is an autosomal-dominant inherited cancer that           alone increases the risk of adenocarcinoma. Estrogen
involves a germline mutation in one of the genes in the       plus progesterone appears to decrease the risk of adeno-
DNA mismatch repair gene family, which includes               carcinoma and therefore is the preferred treatment. In
MSH2, MLM1, and MSH6. Fortunately, HNPCC                      asymptomatic high-risk patients, periodic screening
accounts for only 1% to 5% of all colorectal cancers, but     may be advisable. All postmenopausal women with
it is associated with a 39% to 54% lifetime risk of devel-    uterine bleeding must be evaluated for endometrial
oping colon cancer. There is a lifetime risk of 30% to        cancer, although only 20% of these patients will have a
61% of developing endometrial cancer. There is also an        malignant genital neoplasm. As the patient’s age
increased risk of ovarian cancers and other nongyneco-        increases after menopause, there is a progressively
logic cancers. In a study by Lu and associates, they          increasing probability that her uterine bleeding is caused
noted that about half the time, the endometrial or            by endometrial cancer. Feldman and associates found
ovarian cancer appeared before the colon cancer. In both      that age was the greatest independent risk factor associ-
instances, the age at diagnosis was in the early 40s.         ated with endometrial cancer or complex hyperplasia. In
There was a median of 11 years between the gynecologic        women aged 70 years or older, the odds ratio was 9.1. If
cancer and the colon cancer. About 14% of the time the        complex hyperplasia was present, the odds ratio
gynecologic and colon cancers were diagnosed simulta-         increased to 16. When a woman was older than 70 years,
neously. Several “red flags” should prompt an evalua-         her chance of having cancer when vaginal bleeding was
tion for HNPCC. These include any individual with a           present was about 50%. If she was also nulliparous
personal or family history of colon cancer at an early        and had diabetes, the risk was 87%. A perimenopausal
age of onset (usually before age 50) or endometrial           patient who may have abnormal uterine bleeding indic-
cancer at an early age of onset (premenopausal or before      ative of endometrial cancer is frequently not evaluated
age 50) and two or more HNPCC-related cancers in an           because the patient or her physician interprets her new
individual or family. Assessing a patient’s risk for          bleeding pattern as resulting from menopause. During
hereditary cancer is an important process, beginning          this time in a woman’s life, the menstrual periods should
with screening for the “red flags” of hereditary colon        become lighter and lighter and farther and farther apart.
(and endometrial) cancer. Individuals with any of the         Any other bleeding pattern should be evaluated with
“red flags” should enter into a discussion about genetic      carcinoma of the endometrium in mind. A high index of
testing to determine if this is appropriate for them.         suspicion must be maintained if the diagnosis of endo-
Medical management strategies can be tailored depend-         metrial cancer is to be made in the young patient. Pro-
ing on the genetic testing results and may include            longed and heavy menstrual periods and intermenstrual
increased surveillance, chemoprevention, and prophy-          spotting may indicate cancer, and endometrial sampling
lactic surgery. The Cancer Study Consortium suggests          is advised. Most young patients who develop endome-
colonoscopy every 1 to 3 years beginning at age 25 in         trial cancer are obese, in many instances massively over-
individuals with this hereditary disorder. The data           weight, often with anovulatory menstrual cycles.
suggest that if surveillance is done, survival is improved.      Historically, fractional dilation and curettage (D&C)
Women should be offered surveillance with ultrasound          has been the definitive diagnostic procedure used in
and endometrial sampling from age 25 to 35, although          ruling out endometrial cancer. Today, most advocate the
there are no data to suggest this will improve survival       routine use of the endometrial biopsy as an office proce-
if endometrial cancer is diagnosed by these means. As         dure to make a definitive diagnosis and spare the patient
reported by Schmeler and colleagues, risk-reducing            hospitalization and an anesthetic. Several studies have
surgery consisting of removal of the uterus and bilateral     indicated that the accuracy of the endometrial biopsy in
5.  Adenocarcinoma of the Uterine Corpus	                                     147
detecting endometrial cancer is approximately 90%.           65 primary studies on the use of hysteroscopy to diag-
Cytologic detection of endometrial cancer by routine         nose endometrial cancer and endometrial disease (can­
cervical Papanicolaou (Pap) smear has generally been         cer, hyperplasia, or both), including more than 26,000
poor in comparison with the efficacy of the Pap smear        women. All of the patients had abnormal premeno-
in diagnosing early cervical disease. Several studies in     pausal or postmenopausal uterine bleeding. Using endo-
the literature indicate that only one third to half of the   metrial histologic findings as a reference, a positive
patients with adenocarcinoma of the endometrium have         hysteroscopy result was associated with a 72% probabil-
abnormal Pap smears on routine cervical screening. The       ity of endometrial cancer, whereas a negative result
main reason for the poor detection with the cervical Pap     reduced this probability to 0.6%. The corresponding
smear is that cells are not removed directly from the        probabilities for endometrial disease were 55% with a
lesion as they are on the cervix. When a cytologic prepa-    positive result and 3% with a negative result. The accu-
ration is obtained directly from the endometrial cavity,     racy of hysteroscopy tended to be higher among post-
malignant cells are present in higher numbers than those     menopausal women and in an outpatient setting. They
found if routine cervical or vaginal smears are obtained.    concluded that hysteroscopy is highly accurate and
Techniques that obtain only a cytologic preparation are      thereby clinically useful in diagnosing endometrial
generally inadequate if they are used alone.                 cancer in women with abnormal uterine bleeding and is
    Several commercial apparatuses are available for         moderately useful in diagnosing endometrial disease.
sampling the endometrial cavity on an outpatient basis.      Because many patients with endometrial cancer can be
If diagnosis of endometrial cancer can be made on an         diagnosed with office biopsy, that is our preferred first
outpatient basis, the patient can avoid hospitalization      diagnostic step. If the biopsy result is negative and
and a minor surgical procedure. Devices that remove          further evaluation is needed, we proceed to hysteros-
tissue for histologic evaluation have generally been good    copy. With its use, surgeons can direct biopsies of focal
if tissue is obtained from the endometrial cavity. Stovall   lesions that might be missed by D&C. Hysteroscopy can
and colleagues evaluated 40 patients known to have           also be used to evaluate the endocervical canal.
endometrial cancer with the Pipelle instrument. Ninety          Ultrasonography (US) has been suggested as a diag-
percent of the women were postmenopausal. Only in            nostic tool in evaluating women with irregular bleeding,
one patient was cancer not identified with the Pipelle.      particularly the postmenopausal patient (Figure 5-3).
This patient had a prior D&C that revealed a grade I         The endometrial stripe as seen with transvaginal US
lesion. The Pipelle diagnosis was atypical adenomatous       appears to be indicative of endometrial thickness. Several
hyperplasia, and the hysterectomy specimen revealed a        studies suggest that if a thin endometrial stripe is present,
focus of adenocarcinoma in situ. The pathologist noted       a histologic diagnosis is not necessary because atrophic
that the obtainable tissue was acceptable for analysis in    endometrium would be present. Granberg and associ-
100% of patients. Discomfort was recorded as mild in         ates evaluated 205 women with postmenopausal bleed-
80%, and only two patients (5%) reported severe pain.        ing, 30 postmenopausal asymptomatic women, and 30
Goldchmit and coworkers reported similar accuracy            postmenopausal patients with known endometrial
with the Pipelle in 176 consecutive patients undergoing      cancer. In the two groups of 60 patients, the endometrial
D&C. Whereas endometrial biopsy and D&C appear to            thickness was 3.2 (mean) versus 17.7, respectively. In the
be equivalent in terms of diagnosing cancer, the accuracy    group of 205 women, 18 were found to have endometrial
of endometrial biopsy appears to be inferior to D&C in       cancer. No cancers were present in the endometrium that
predicting final posthysterectomy tumor grade. In a          had an endometrial thickness of 8 mm or less. There was
recent study by Leitao and colleagues, 18% of endome-        considerable overlap of endometrial thickness by all
trial biopsy specimens were upgraded on final hysterec-      histologic groups. The authors noted that if a cutoff of
tomy specimen, whereas only 9% of D&C specimens              5 mm was used, no false-negative findings were present.
were upgraded. In the symptomatic patient in whom            With this measurement, the positive predictive value
inadequate tissue (or no tissue at all) is obtained for      was 87%, with specificity of 96% and sensitivity of 100%
pathologic evaluation, a D&C must be considered.             for identifying endometrial abnormalities. It has been
    Hysteroscopy has been suggested as adjuvant in           suggested that if US could save a large number of endo-
making the diagnosis of endometrial cancer and in            metrial biopsies, there would be a large cost savings
establishing the extent of disease. Hysteroscopy has         with less discomfort to the patient. As previously noted,
been used frequently in the evaluation of patients with      significant pain with the newer disposable endometrial
abnormal uterine bleeding and has the advantages of          biopsy techniques affects only a small number of patients;
allowing the physician to see the pathologic lesion and      and a certain number of patients, because of consider-
direct biopsy, identify other competing diagnoses            able endometrial thickness, will require endometrial
(fibroids, polyps), and perform the procedure on an out-     sampling anyway. Clark and colleagues investigated
patient basis. Clark and colleagues analyzed data from       the cost-effectiveness of initial diagnostic strategies for
148	                                           5.  Adenocarcinoma of the Uterine Corpus




                         A




B                                                            C

FIGURE 5-3  A, Ultrasound of the uterus showing the “triple line” indicating the thickness of the endometrium. B, Ultrasound of the uterus
showing a “thickened endometrium” of more than 10 mm. C, Saline instillation of the endometrial cavity notes a well-defined submucous fibroid
and not thickened endometrium.




postmenopausal bleeding. A decision analytic model                      reviews, clinical outcomes from published literature and
was constructed to reflect current service provision,                   cost estimates from local and National Health Service
which evaluated 12 diagnostic strategies using endome-                  sources. The main outcome measure was the cost per
trial biopsy, ultrasonography (4- and 5-mm endometrial                  additional life year gained (£/LYG). Compared with car-
thickness cutoff), and hysteroscopy. Diagnostic probabil-               rying out no initial investigation, a strategy based on
ity estimates were derived from systematic quantitative                 initial diagnosis with US using a 5-mm cutoff was the
5.  Adenocarcinoma of the Uterine Corpus	                                   149
least expensive (£11 470/LYG). Initial investigation with   endometrial thickness on US of 5 mm or more versus
endometrial biopsy or US using a 4-mm cutoff was com-       19% in the non-tamoxifen group (51% vs 8% more than
parably cost-effective (<£30 000/LYG vs US with a 5-mm      10 mm, respectively). Hysteroscopy findings noted that
cutoff). The strategies involving initial evaluation with   28% of uterine mucosa was atrophic versus 87% in the
test combinations or hysteroscopy alone were not cost-      non-tamoxifen control group. Histopathologic examina-
effective. They concluded that women presenting for the     tion noted atrophic endometrium in 60% of tamoxifen-
first time with postmenopausal bleeding should undergo      treated patients versus 79% of control subjects. The
initial evaluation with US or endometrial biopsy.           biggest difference between the two groups was the
   Unfortunately, endometrial cancer has been identified    finding of polyps in 18% of the tamoxifen group versus
when the endometrial thickness is less than 5 mm.           0% of the control group; this appears to be a frequent
Although studies may evaluate several hundred patients,     finding in the tamoxifen-treated patient. So-called mega-
most do not have many cancer patients included. Wang        polyps measuring up to 12 cm have been described.
and associates reviewed the ultrasound of 52 women          Other uterine disease has been attributed to tamoxifen,
who were diagnosed with papillary serous clear cell and     including increased uterine volume, lower impedance to
other high-grade carcinomas. Of the 52, 34 (65%) had        blood flow in uterine arteries, endometriosis, focal peri-
thickened endometrium measuring 5 mm or more; in 9          glandular condensation of stromal cells, and epithelial
(17%) the endometrium was less tham 5 mm, and in an         metaplasia. Data now suggest that the markedly thick-
additional 9 women (17%) the endometrium was indis-         ened endometrium (up to 40 mm) in patients receiving
tinct. In the women with nonthickened endometrium,          tamoxifen is not thickened endometrium but proximal
other ultrasound abnormalities were noted: intracavi-       myometrium.
tary fluid or lesion, myometrial mass, enlarged uterus,        US has also been evaluated as a means for determin-
or adnexal mass. Multiple factors can affect endometrial    ing depth of myometrial invasion. Gordon and associ-
thickness. These include estrogen, estrogen plus proges-    ates studied 15 known patients with endometrial cancer
tin, body mass index (BMI), diabetes, poor histotype,       by US and magnetic resonance imaging (MRI). By use of
race, and postmenopausal status. The Committee on           criteria of greater than 50% myometrial wall involve-
Gynecologic Practice of the American College of Obste-      ment as deep invasion and less than 50% as superficial
tricians and Gynecologists issued an opinion on the role    invasion, US was judged to be more accurate than MRI
of transvaginal ultrasonography in the evaluation of        in five studies; MRI was better in three, both were equally
postmenopausal bleeding. They concluded that women          accurate in four, and neither was accurate in three. It has
with postmenopausal bleeding may be assessed initially      been suggested by some that US can accurately predict
with either endometrial biopsy or transvaginal ultraso-     myometrial invasion in about 75% of cases. Although
nography. This initial evaluation does not require per-     knowing the depth of invasion preoperatively would be
formance of both tests. Transvaginal ultrasonography        important information to the clinician, the data from
can be useful in the triage of patients in whom endome-     studies as noted before would currently appear to be too
trial sampling was performed but tissue was insufficient    premature or too costly to use routinely. We prefer to
for diagnosis. When transvaginal ultrasonography is         evaluate depth of myometrial invasion intraoperatively
performed for patients with postmenopausal bleeding         with gross examination or frozen section.
and an endometrial thickness of less than or equal to
4 mm is found, endometrial sampling is not required.
                                                            Pathology
Meaningful assessment of the endometrium by ultraso-
nography is not possible in all patients. In such cases,    Careful evaluation of the uterus by the pathologist is
alternative assessment should be completed. When            essential for proper diagnosis and treatment of corpus
bleeding persists despite negative initial evaluations,     cancer (Figure 5-4). Gross inspection of a bivalved uterus
additional assessment is indicated.                         at the time of hysterectomy can offer an impression of
   The reliability determining endometrial thickness in     the size of the lesion, its location (involvement of fundus,
the postmenopausal patient does not appear to be appli-     lower uterine segment, or cervix), and depth of tumor
cable to women taking tamoxifen. In all studies, the        penetration into the myometrium (depth of invasion). A
endometrium in the tamoxifen-treated patient is consid-     clinically enlarged uterus may be caused by increasing
erably thicker than in the non–tamoxifen-treated patient.   tumor volume, but this should not be the only gauge for
Histologic evaluation revealed atrophic endometrium         significant local disease. Obviously, many patients can
in a large number of these tamoxifen-treated patients.      have enlarged uteri because of factors other than adeno-
Lahti and colleagues evaluated 103 asymptomatic post-       carcinoma. Carcinoma of the endometrium may start as
menopausal patients (51 receiving tamoxifen and 52          a focal discrete lesion, as in an endometrial polyp. It may
control subjects) with US, hysteroscopy, and endometrial    also be diffuse in several different areas, in some situa-
histologic examination. In the tamoxifen group, 84% had     tions involving the entire endometrial surface. As the
150	                                            5.  Adenocarcinoma of the Uterine Corpus

                                                                     TABLE 5-3  Endometrial Carcinoma Subtypes
                                                                     Type                                                       Number (%)
                                      11
                                           12                        Endometrioid                                               6231 (84)
                                                13                   Adenosquamous                                               317 (4.2)
                         5
                                                      14             Mucinous                                                     74 (0.9)
                     4                                               Papillary serous                                            335 (4.5)
                                                                     Clear cell                                                  185 (2.5)
                 3                                                   Squamous cell                                                28 (0.04)
                                                                     Other                                                       285 (3.8)
                 2
                                                 10                  From Pecorelli S (ed): Int J Gynecol Obstet 83:79, 2003.
                 1                         9
                                      8
                                 7
                             6
                                                                     of patients. Historically, patients with a squamous com-
                                                                     ponent were further stratified according to whether the
                                                                     squamous component appeared benign (designated
                                                                     adenoacanthoma, AA) or malignant (designated adeno-
                                                                     squamous carcinoma, AS). It was suggested that AA
                                                                     indicated a good prognosis, and those with AS had a
                                                                     poor survival. Today, this distinction has been ques-
FIGURE 5-4  Pathologic evaluation of endometrial cancer. (Courtesy
                                                                     tioned in regard to its prognostic importance. Zaino and
Paul Underwood, MD.)                                                 co-workers, in reporting data from the GOG, suggest
                                                                     that the notation of squamous component irrespective of
                                                                     differentiation does not affect survival. Patients with
tumor grows, it can become larger and/or spread within               clinical stage I and stage II cancers were evaluated, and
the endometrium or myometrium. Endometrial cancer                    456 with typical adenocarcinoma (AC) and 175 with
may disseminate to regional lymph nodes, by emboliza-                squamous differentiation (AC + SQ) were identified. The
tion or direct extension into the pelvis or vagina, or               latter were subdivided into 99 with AA and 69 with AS.
hematogenously to distant organs (Figure 5-5). The risk              Multiple known prognostic factors were compared with
of spread is related to several factors, including depth of          differentiation of glandular and squamous component
invasion into the myometrium, tumor grade, and histo-                of the tumor. Age, depth of myometrial invasion, archi-
logic type.                                                          tecture, nuclear grade, and combined grade were similar
    Adenocarcinoma, the most common histologic type,                 for AC and AC + SQ, although patients with AA were
is usually preceded by a predisposing lesion, atypical               better differentiated than those with AS and had less
endometrial hyperplasia (Table 5-3). Only those hyper-               myometrial invasion. Both glandular and squamous dif-
plasias with cellular atypia are considered to be precur-            ferentiation correlated with frequency of pelvic and
sors of adenocarcinoma of the endometrium. For most                  para-aortic node metastasis. Nodal metastasis, when it
patients with endometrioid-type tumors, particularly                 was stratified for grade and depth of invasion, was
grade I-II lesions, and hyperplasia, hyperestrogenism is             similar in AC and AC + SQ patients. The differentiation
the etiologic basis. Pathologically, endometrial cancer is           of squamous component is closely correlated with the
characterized by the presence of glands in an abnormal               differentiation of the glandular element, and the glandu-
relationship to each other, with the hallmark of little if           lar element is a better predictor of outcome. It would
any intervening stroma between the glands. There can                 therefore appear that the previous designation of AA
be variations in the size of the glands, and infolding is            and AS has no added predictive property than differen-
common. The cells are usually enlarged, as are the nuclei,           tiation of glandular component and probably should
along with nuclear chromatin clumping and nucleolar                  be dropped as a diagnostic term. The authors suggest
enlargement. Mitosis may be frequent. Differentiation of             the term squamous differentiation instead, with differ-
adenocarcinoma (mild, moderate, and severe, or grades                entiation of the glandular component noted as the
I-III) is important prognostically and is incorporated into          important prognostic factor. Subsequently, Abeler and
FIGO surgical staging (Figure 5-6). Most studies suggest             Kjorstad reviewed 255 cases and made the same
that 60% to 65% of all endometrial cancers are of this               recommendations.
subtype.                                                                Secretory adenocarcinoma (Figure 5-7) is an uncom-
    For almost a century, it has been recognized that a              mon type of endometrial cancer. It usually represents
squamous component may be associated with an adeno-                  well-differentiated carcinoma with progestational
carcinoma of the endometrium. This occurs in about 25%               changes. It is difficult to differentiate it from secretory
5.  Adenocarcinoma of the Uterine Corpus	                                                 151

           Endometrium                      Stage Ia                                     Endocervical
              Stage Ib                         Stage Ic                                  glands

                                                                                        Myometrium
                                                                         Stage IIb                          Stage IIa


                                                                            Stage IIb                  Stage IIa
                                                                                                       Endocervical
                                                                                                       stroma

                                                                                        Endocervical
                                                                                        canal




          Stage Ia: Tumor limited to endometrium                       Stage IIa: Endocervical glandular involvement only
          Stage Ib: Invasion to less than half the myometrium          Stage IIb: Cervical stroma invasion
          Stage Ic: Invasion to more than half the myometrium
                               Stage I                                                    Stage II
                                                                                          Pelvic                      Periaortic
                                                                                          nodes                       nodes




    Positive
    cytology




               Stage IIIA                                 Stage IIIB                                         Stage IIIC
                                                                Omentum




                                                                                  Inguinal nodes


                                Stage IVa                                               Stage IVb
152	                                               5.  Adenocarcinoma of the Uterine Corpus


                                         Pelvic Organs                                 Lymph Nodes



                                                                                   Aortics

                                                                                      Common iliacs
                            Loose cancer cells                                                Hypogastrics
                            in peritoneal cavity
                                                                                                 External
                                                                                                 iliacs


                           Small bowel
                           implants




                           Involved
                           ovary

                           Extension to
                           broad ligament
                                                                                                  Obturator




                           Vaginal                                                                Inguinals

                                                                                                  Paracervical

FIGURE 5-5  Spread pattern of endometrial cancer with particular emphasis on potential lymph node spread. Pelvic and periaortic nodes are
at risk, even in stage I disease.




endometrium. Survival is good and comparable to that                    that has a propensity for vascular or lymphatic vascular
associated with the pure adenocarcinoma. Although it is                 space involvement (LVSI). Well-formed papillae are
an interesting histologic variant, the separation of the                lined by neoplastic cells with grade III cytologic features
entity as it relates to treatment and survival is probably              (Figure 5-8). Differentiation between papillary architec-
not warranted.                                                          ture and syncytial metaplasia with benign endometrial
   Increasing emphasis has been placed on the impor-                    alterations must be made because the papillary architec-
tance of the histologic subtype serous adenocarcinoma                   ture alone does not designate PS. The uterus may appear
(SC) of the uterus (also called uterine papillary serous                grossly normal but can have extensive myometrial inva-
carcinoma, UPSC). This subtype represents less than                     sion. Most UPSC tumors are aneuploid and have a
10% of all adenocarcinomas but is a highly aggressive                   high S-phase. Serous cancers can be pure or admixed
carcinoma of the uterus. Unlike the more common vari-                   with other histologic types (endometrioid, clear cell,
ants, PS is not associated with hyperestrogenism and                    carcinosarcoma).
frequently develops in the setting of atrophic endome-                     Clear cell carcinomas (Figure 5-9) are also infrequent
trium. It is more commonly seen in older and nonwhite                   in number but have distinct histologic criteria. Clear cell
patients. Hendrickson, in the early 1980s, noted that in                tumors are characterized by large polyhedral epithelial
more than 250 endometrial cancers, only 10% had histo-                  cells that may be admixed with typical non–clear
logic features of SC, but these accounted for 50% of                    cell adenocarcinomas. Some authorities accept the
all treatment failures. The histopathologic appearance                  mesonephritic-type hobnail cells as part of this pattern,
resembles a high-grade serous carcinoma of the ovary                    whereas others believe that this histologic type should
5.  Adenocarcinoma of the Uterine Corpus	                                              153




    A

                                                                       FIGURE 5-7  High-power view of well-differentiated secretory car-
                                                                       cinoma invading inner one-third of the myometrium. (Courtesy William
                                                                       M. Christopherson, MD, Louisville, Kentucky.)




    B




                                                                       FIGURE 5-8  Serous adenocarcinoma. Similarity to ovarian carci-
                                                                       noma is apparent. (Courtesy Gregory Spiegel, MD.)




    C

FIGURE 5-6  Histologic patterns of differentiation in endometrial
carcinoma. A, Well-differentiated (G1). B, Moderately differentiated
(G2). C, Poorly differentiated (G3). (Courtesy Gregory Spiegel, MD.)




                                                                       FIGURE 5-9  Clear cell carcinoma of the endometrium. Clear cell
                                                                       component is quite evident. (Courtesy Gregory Spiegel, MD.)
154	                                                       5.  Adenocarcinoma of the Uterine Corpus


be excluded from the clear cell category. Silverberg and                                    grade, raises the grade of a grade I or grade II tumor by
DeGiorgi and Kurman and Scully suggested a worse                                            one. By convention, serous and clear tumors are consid-
prognosis for clear cell adenocarcinoma than for pure                                       ered grade III/high-grade tumors.
adenocarcinoma. This was confirmed in studies by
Christopherson and co-workers. Even in stage I disease,
only 44% of patients with clear cell carcinomas survive                                                   PROGNOSTIC FACTORS
5 years. Neither the FIGO classification nor nuclear
grade correlates with survival. Photopulos and associ-                                      Following hysterectomy and lymph node dissection,
ates, in a review of their material, noted that their patients                              clinical-pathologic characteristics are commonly used to
with this entity were older and tended to have a worse                                      predict risk of recurrence and to optimize therapy. Mul-
prognosis. They did note that patients with stage I clear                                   tiple factors have been identified for endometrial carci-
cell carcinomas had a 5-year survival similar to that of                                    noma that have prognostic value (Table 5-4). Essentially
patients with stage I pure adenocarcinoma of the                                            all reports in the literature agree stage (extent of disease
endometrium.                                                                                spread), grade of tumor, and depth of invasion are
                                                                                            important prognostic considerations. Before 1988 endo-
                                                                                            metrial cancer was clinically staged with stage assign-
Tumor Grade                                                                                 ments based on uterine size and clinical extent of disease.
In addition to histologic type, pathologists assign a                                       Because of the considerable discrepancy between the
measure of tumor differentiation, known as grade, to                                        clinical extent of disease spread and pathologic spread
endometrial cancers. Grade I lesions are well differenti-                                   noted after surgical staging, FIGO adopted a surgical-
ated, are frequently associated with estrogen excess,                                       pathologic staging classification in 1988. In 2009 FIGO
closely resemble hyperplastic endometrium, and are                                          updated the staging system (Table 5-5). FIGO staging
generally associated with a favorable prognosis. Grade                                      classification attempts to categorize patients into prog-
III lesions are poorly differentiated, do not resemble                                      nostic groups based on extent of disease and tumor
normal endometrium, and frequently have a poorer                                            grade.
prognosis. Grade II tumors are moderately well differ-
entiated and have an intermediate prognosis. Both archi-
tectural criteria and nuclear grade are used to classify.
Architectural grade is related to the proportion of solid
tumor growth, with grade I having an adenocarcinoma                                         TABLE 5-4  Prognostic Factors in Endometrial Adenocarcinoma
in which less than 5% of the tumor growth is in solid
                                                                                            Histologic type (pathology)
sheets, grade II has 6% to 50% of the neoplasm arranged                                     Histologic differentiation
in solid sheets of neoplastic cells, and grade III has                                      Stage of disease
greater than 50% of the neoplastic cells in solid masses.                                   Myometrial invasion
Regions of squamous differentiation are excluded from                                       Peritoneal cytology
                                                                                            Lymph node metastasis
this assessment. The FIGO rules for grading state that
                                                                                            Adnexal metastasis
notable nuclear atypia, inappropriate for architectural


TABLE 5-5  2009 FlGO Staging System for Carcinoma of the Endometrium

Stage I*   Tumor contained to the corpus uteri
           IA   No or less than half myometrial invasion
           IB   Invasion equal to or more than half of the myometrium
Stage II        Tumor invades the cervical stroma but does not extend beyond the uterus†
Stage III*      Local and/or regional spread of tumor‡
           IIIA Tumor invades the serosa of the corpus uteri and/or adnexas
           IIIB Vaginal and/or parametrial involvement
           IIIC Metastases to pelvis and/or para-aortic lymph nodes
                IIICl Positive pelvic nodes
                IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph nodes
Stage IV*       Tumor invades bladder and/or bowel mucosa and/or distant metastases
           IVA Tumor invasion of bladder and/or bowel mucosa
           IVB Disant metastases, including intra-abdominal metastases and/or inguinal lymph nodes

*Includes grades 1, 2, or 3.
†
  Endocervical glandular involvement only should be considered as stage I and no longer as stage II.
‡
  Positive cytology has to be reported separately without changing the stage.
5.  Adenocarcinoma of the Uterine Corpus	                                         155

Stage of Disease: Depth of Invasion, 	                                                       care for patients with endometrial cancer. GOG protocol
Cervical Involvement, Adnexal Involvement,                                                   33 was a surgical-pathologic study of 621 patients with
                                                                                             clinical stage I endometrial cancer who were uniformly
and Nodal Metastasis
                                                                                             treated with total abdominal hysterectomy, bilateral
Staging of patients with malignancies is designed to                                         salpingo-oophorectomy, peritoneal cytologic evaluation,
have prognostic value by classifying the size and extent                                     and selective pelvic and para-aortic selected lymphad-
of tumor. The survival rate in regard to stage of disease                                    enectomy. Before this study, it was presumed most
has been consistent, and Table 5-6 and Figure 5-10 show                                      patients with endometrial cancer were at risk for nodal
the 5-year survival rate reported by FIGO (FIGO 1988                                         metastases and nearly all patients required some form
staging). The patterns of disease spread in endometrial                                      of pelvic radiation therapy (either preoperatively or
cancer was evaluated in a prospective study performed                                        postoperatively). The study demonstrated important
by the GOG (GOG protocol 33) and reported by Creas-                                          relationships between pathologic factors and risk of
man. This study is required reading for physicians who                                       nodal disease. For example, factors associated with
                                                                                             nodal disease included higher tumor grade, deeper
                                                                                             myometrial invasion, cervical involvement, (+) cytology,
TABLE 5-6 Five-Year Survival in Endometrial Cancer: Surgical                                 and LVSI. As a result of this study FIGO accepted a
Stage                                                                                        surgical-based staging system of endometrial cancer in
                                                                                             1988.
Stage                 No. of Patients                           Five-Year Survival (%)
                                                                                                For endometrial cancer, FIGO staging reflects the pro-
      Ia                                1063                             91                  gression of disease within the uterus and at extrauterine
      Ib                                2735                             90                  sites. Approximately 75% of patients with endometrial
      Ic                                1219                             81
                                                                                             cancer present with disease limited to the uterus (Table
     IIa                                 364                             79
     IIb                                 426                             71                  5-7). For stage I disease, depth of tumor invasion into the
    IIIa                                 484                             60                  myometrium is an important prognostic factor. The
    IIIb                                  73                             30                  degree of myometrial invasion is a consistent indicator
    IIIc                                 293                             52                  of tumor virulence (Figure 5-11). DiSaia and associates
    IVa                                   47                             15                  noted that recurrences were directly related to depth of
    IVb                                  160                             17
                                                                                             myometrial invasion in patients with stage I cancer
From Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003.                                     treated primarily with surgery (Table 5-8). The Annual


                                                  100

                                                                                                                    Stage Ia (n ϭ 1063)
                                                                                                                    Stage Ib (n ϭ 2735)
                                                                                                                    Stage Ic (n ϭ 1219)
                                                   80                                                               Stage IIa (n ϭ 364)
                                                                                                                    Stage IIb (n ϭ 426)
                           Proportion surviving




                                                                                                                    Stage IIIa (n ϭ 484)
                                                   60

                                                                                                                    Stage IIIc (n ϭ 293)

                                                   40                                                               Stage IIIb (n ϭ 73)




                                                   20                                                               Stage IVb (n ϭ 150)
                                                                                                                    Stage IVc (n ϭ 47)



                                                   0
                                                        0   1             2              3           4          5

                                                                                    Years after diagnosis

FIGURE 5-10  Carcinoma of the corpus uteri; patients treated in 1990–1992 (FIGO). Survival by surgical stage (n = 5694). [From Pecorelli S (ed):
Int J Gynecol Obstet 83:95, 2003. © International Federation of Gynecology and Obstetrics.]
156	                                                        5.  Adenocarcinoma of the Uterine Corpus

TABLE 5-7 Distribution of Endometrial Carcinoma by Stage                           TABLE 5-8  Relationship between Depth of Myometrial
(Surgical)                                                                         Invasion and Recurrence in Patients with Stage I Endometrial
                                                                                   Carcinoma
Stage                                                               Patients (%)
                                                                                   Endometrial only                                                      7/92 (8%)
    I                                                                 3839 (73)    Superficial myometrium                                               10/80 (13%)
   II                                                                  574 (11)    Medium myometrium                                                     2/17 (12%)
  III                                                                  694 (13)    Deep myometrium                                                      15/33 (46%)
  IV                                                                   166 (3)
                                                                                   Modified from DiSaia PJ et al: Am J Obstet Gynecol 151:1009, 1985.
From Pecorelli S (ed): J Epidemiol Biostat 3:41, 1998.




                             Myometrial invasion                                   TABLE 5-9  Relationship between Depth of Myometrial
                                                                                   Invasion and Five-Year Survival Rate (Stage I)
                   Endometrium         Inner             Outer    Cervical or
                      only              half              half   extrauterine      Stage                       Patients                       5-Year Survival (%)
                                                                 involvement
                                                                                   IaG1                           698                                    93
        Grade 1                                                                    IbG1                          1030                                    88
                                                                                   IcG1                           442                                    87
        Grade 2                                                                    IaG2                           229                                    91
                                                                                   IbG2                          1307                                    93
        Grade 3                                                                    IcG2                           485                                    84
                                                                                   IaG3                            66                                    75
                 Low risk            Intermediate risk           High risk         IbG3                           280                                    82
                                                                                   IcG3                           247                                    66
FIGURE 5-11  Risk assignment based on surgical staging/extent of
disease in patients with endometrial cancer.                                       From Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003.




Report of FIGO demonstrated a decrease in the survival                             than do those with only fundal disease (8%). There is a
rate as myometrial penetration increased (Table 5-9).                              similar frequency of para-aortic nodal metastases: a 16%
Lutz and co-workers determined that the depth of myo-                              incidence from disease of the lower uterine segment and
metrial penetration was not as important as the proxim-                            a 4% incidence when only fundal disease is present.
ity of the invading tumor to the uterine serosa. Patients                          Previously, endocervical curettage (ECC) was commonly
whose tumors invaded to within 5 mm of the serosa had                              used to determine whether the patient had cervical
a 65% 5-year survival rate, whereas patients whose                                 involvement. Many false-positive results occur through
tumors were more than 10 mm from the serosa had a                                  the use of this technique, however. In addition, the prog-
97% survival rate. The depth of myometrial invasion is                             nostic significance of endocervical glandular spread (for-
associated with the other prognostic factors, such as the                          merly stage IIa) has been challenged. The new surgical
grade of the tumor. As noted by DiSaia and associates,                             staging adopted by FIGO in 2009 includes only those
the survival rate of patients with poorly differentiated                           patients with cervical stromal invasion in the stage II
lesions and deep myometrial invasion is poor in contrast                           category. In some cases, cervical biopsy and/or ECC is
to that of patients who have well-differentiated lesions                           required in the pretreatment planning of a patient with
but no myometrial invasion. This suggests that virulence                           suspected cervical involvement.
of the tumor may vary considerably, and as a result,                                  Patients with stage III-IV disease may have a hetero-
therapy should depend on the combination of prognos-                               geneous mix of disease characteristics. It is well recog-
tic factors.                                                                       nized that endometrial cancer can and frequently does
   Location of the tumor within the endometrial cavity                             metastasize to the adnexa. Patients with adnexal and/
is important because tumors low in the cavity may                                  or serosal involvement are categorized as stage IIIA and
involve the cervix earlier than fundal lesions. Prognosis                          are considered to have a higher risk of peritoneal recur-
for women with cervical involvement (stage II) is worse                            rence. In GOG 33, 5% of patients had adnexal involve-
than with stage I disease. Cervical involvement is often                           ment. Adnexal metastasis was significantly associated
a surrogate marker for extrauterine disease spread or for                          with involved pelvic (32%) and para-aortic (20%) lymph
risk of local recurrence. Data from GOG 33 showed that                             nodes. In a large surgical trial comparing laparoscopy
those with disease of the lower uterine segment had a                              to open staging (GOG Lap 2 trial), 5% of 2616 patients
higher incidence of pelvic lymph node metastases (16%)                             enrolled were found to have stage IIIA disease (FIGO
5.  Adenocarcinoma of the Uterine Corpus	                                              157
TABLE 5-10  Grade vs Positive Pelvic and Aortic Nodes                          TABLE 5-12 Frequency of Pelvic and Para-Aortic Nodal Disease
Grade (n)                Pelvic Nodes (%)                   Aortic Nodes (%)                                                      Grade

G1 (180)                       5 (3)                             3 (2)                                       Grade I            Grade II    Grade III
G2 (288)                      25 (9)                            14 (5)         Depth of Invasion             (n = 180)          (n = 288)   (n = 153)
G3 (153)                      28 (18)                           17 (11)
                                                                               Endometrial only                0%/0%             3%/3%       0%/0%
Modified from Creasman WT et al: Cancer 60:2035, 1987.                           (n = 86)
                                                                               Inner one-third                 3%/1%             5%/4%       9%/4%
                                                                                 (n = 281)
                                                                               Middle one-third                0%/5%             9%/0%       4%/0%
                                                                                 (n = 115)
TABLE 5-11 Maximal Invasion and Node Metastasis                                Outer one-third               11%/6%             19%/14%     34%/23%
                                                                                 (n = 139)
Maximal invasion (n)              Pelvic Nodes (%)          Aortic Nodes (%)
                                                                               (Pelvic Nodal Positivity/Para-aortic Nodal Positivity)
Endometrium only (87)                    1 (1)                   1 (1)         Modified from Creasman WT et al: Cancer 60:2035, 1987.
Superficial muscle (279)                15 (5)                   8 (3)
Intermediate muscle (116)                7 (6)                   1 (1)
Deep muscle (139)                       35 (25)                 24 (17)

Modified from Creasman WT et al: Cancer 60:2035, 1987.
                                                                               tumors had pelvic nodal metastases of 3%, 9%, and 18%
                                                                               respectively. Similarly, patients with no myometrial
                                                                               invasion, inner one third, middle one third, and outer
1988 staging). In an analysis of 222 patients with clinical                    one third invasion had 1%, 5%, 6%, and 25% pelvic nodal
stage I carcinoma of the endometrium reported by                               disease, respectively. The highest risk group included
DiSaia and colleagues, 16 (7%) were found to have                              patients with grade III tumors and outer one third inva-
metastasis in the adnexa. This finding correlated with                         sion who had pelvic nodal involvement in 34% of cases
many but not all of the other prognostic factors. Spread                       (Table 5-12). Without a lymphadenectomy, one may
to the adnexa did not seem to be related to the size of                        grossly estimate the probability of nodal involvement
the uterus. The grade of the disease did not appear                            based on these data to select for or against the use of
prognostically important in regard to this in that 6% of                       adjuvant therapy. This strategy potentially results in
patients with grade I tumors had adnexal disease com-                          undertreatment or overtreatment of patients, however.
pared with only 10% if poorly differentiated carcinoma                         In two large prospective randomized trials, routine
was present. The depth of invasion did appear to be                            lymphadenectomy resulted in the identification of more
significant, however, in that only 4% of patients with                         patients with nodal disease (9% to 13%), compared to
only the endometrium involved had adnexal spread,                              when only clinically suspicious nodes were removed
compared with 24% who had adnexal metastases if                                (1% to 3%). It is clear that patients with nodal disease
deep muscle was involved. If tumor was limited to the                          have poorer prognosis (3- to 5-year survival of 50% to
fundus of the uterus, only 5% of patients had disease                          75%) and different patterns of failure (nodal, distant)
in the adnexa; however, if the lower uterine segment or                        than patients with negative nodes (3- to 5-year survival
the endocervix was involved, one-third had spread to                           of 80% to 95%, vaginal cuff failures predominate).
the adnexa. When metastasis was present in the adnexa,                         Patients with nodal involvement include those with
60% of patients had malignant cells in the peritoneal                          pelvic nodal disease (IIIC1) or any para-aortic involve-
cytologic fluid, compared with only 11% if the adnexa                          ment (IIIC2). The substaging was created in 2009 given
were not involved. Recurrences appeared in only 14%                            the belief of different outcomes associated with different
of these individuals who did not have metastasis to the                        levels of nodal involvement. The number of involved
adnexa, compared with recurrences in 38% of patients                           nodes and the extent of resection of grossly involved
with adnexal metastasis.                                                       nodes also affect outcome. In addition Mariani and
   Metastatic spread to lymph nodes (stage IIIC) has                           McMeekin have suggested that patients with (+) nodal
prognostic and therapeutic implications. It is clear that                      disease plus other stage III defining features (positive
lymphadenectomy is the most sensitive way to identify                          cytology, adnexal or serosal involvement) have a much
nodal disease. The GOG 33 study demonstrated that as                           poorer prognosis than those with nodal disease only.
the depth of tumor invasion or tumor grade increased,                          Patients with stage IV/distant disease spread (intraperi-
the frequency of pelvic and para-aortic nodal metastases                       toneal, lung, liver) have a particularly poor prognosis,
also increased (Tables 5-10 and 5-11). For all 621 patients,                   with 5-year survival of less than 20%. The extent of sur-
58 (9%) had positive pelvic nodes and 34 (6%) had posi-                        gical resection has been suggested to alter prognosis in
tive para-aortic nodes. Patients with grade 1, 2, and 3                        patients with advanced-stage disease. As with ovarian
158	                                                     5.  Adenocarcinoma of the Uterine Corpus


cancer, the extent of resection of disease reflects biology                           invasion, whereas patients with a poorly differentiated
of the tumor, aggressiveness of the surgery, and response                             malignant neoplasm might have only endometrial or
to postoperative therapies.                                                           superficial myometrial involvement.

                                                                                      Lymphovascular Space Involvement
Tumor Grade                                                                           Hanson and colleagues described 111 patients with stage
The degree of histologic differentiation (tumor grade) of                             I endometrial cancer and found capillary-like space
endometrial cancer is a sensitive indicator of prognosis                              (CLS) involvement in 16. This was most frequently
and is included in FIGO stage assignment. The Annual                                  found in patients with poorly differentiated tumors with
Report on the Results of Treatment in Gynecological                                   deep invasion. These patients had a 44% recurrence rate,
Cancer has evaluated survival in regard to grade in                                   compared with 2% if the CLS was not involved. This was
patients with clinical stage I adenocarcinoma of the                                  an independently significant prognostic factor. In the
endometrium (Table 5-13). Tumor grade is inversely                                    GOG study of 621 patients, it was shown that 93 (15%)
related to survival decreases; as grade increases, survival                           had CLS involvement. The incidences of pelvic and
is poorer. In their review of 244 patients with stage I                               para-aortic node metastases were 27% and 19%, respec-
disease, Genest and colleagues noted that patients with                               tively. This compares with a 7% occurrence of pelvic
grade I disease had a 5-year survival rate of 96%. This                               node metastasis and a 3% occurrence of para-aortic node
dropped to 79% and 70% for grade II and grade III,                                    metastasis when there is no CLS involvement. In risk
respectively. Data presented by Morrow for outcomes in                                models predicting risk of recurrence in node-negative/
patients enrolled on GOG 33 show that recurrence-free                                 early-stage endometrial cancer, the GOG has suggested
survival markedly diminishes with increasing grade,                                   that LVSI is an important risk factor. In the Post Opera-
with progression-free survival (PFS) at 48 months being                               tive Radiation Therapy in Endometrial Cancer (PORTEC)
approximately 95%, 85%, and 68% for grade I, II, and III                              trial, LVSI was considered to be a factor associated with
tumors, respectively. Grade of tumor also correlates with                             distant site of failure.
other factors of prognosis. Table 5-14 shows the relation-
ship between differentiation of the tumor and depth of                                Tumor Size
myometrial invasion as reported by Creasman from the                                  Schink and co-workers evaluated tumor size in 91
GOG 33 study. As the tumor becomes less differentiated,                               patients with stage I disease. The incidence of lymph
the chances of deep myometrial involvement increase.                                  node metastases in patients with tumor size less than
However, exceptions can occur: Patients with a well-                                  2 cm was only 6%. If tumor was greater than 2 cm in
differentiated lesion can have deep myometrial                                        diameter, there were nodal metastases of 21% and up to
                                                                                      40% if the entire endometrium was involved. Patients
                                                                                      with lesions greater than 2 cm in size and less than half
                                                                                      myometrial invasion had no nodal metastasis. Using
TABLE 5-13  Relationship between Tumor Differentiation                                multivariate analysis, the authors showed that tumor
and Five-Year Survival Rate, Stage I (Surgical)
                                                                                      size was an independently significant prognostic factor.
Grade                                                 Survival (n = 5017) (%)         Watanabe and associates did not find cancer size was
                                                                                      predictive of lymph node metastasis. Gynecologic oncol-
   1                                                               91
   2                                                               90                 ogists from the Mayo Clinic have developed a risk model
   3                                                               81                 predicting nodal metastases and have suggested that
                                                                                      grade I-II tumors that are less than 2 cm are particularly
From Pecorelli S (ed): FIGO Annual Report, years 1996–98, Int J Gynecol Obstet
83:95, 2003.
                                                                                      low risk for nodal disease.

                                                                                      Peritoneal Cytology
                                                                                      The importance of peritoneal cytology in endometrial
TABLE 5-14  Correlation of Differentiation and Myometrial                             cancer is controversial. In GOG 33, 76 (12%) had malig-
Invasion in Stage I Cancer                                                            nant cells identified by cytologic examination of perito-
                                                         Grade                        neal washings. Of these patients, 25% had positive pelvic
                                                                                      nodes, compared with 7% of patients in whom no malig-
Myometrial Invasion                   1 (%)              2 (%)              3 (%)
                                                                                      nant cells were found in peritoneal cytologic specimens
None                                    24                 11                    11   (P > 0.0001). It is true that peritoneal cytology, to a certain
Superficial                             53                 45                    35   degree, mimics other known prognostic factors—that is,
Mid                                     12                 24                    16   if peritoneal cytologic specimens are positive, other
Deep                                    10                 20                    42
                                                                                      known poor prognostic factors may also be identified.
Modified from Creasman WT et al: Cancer 60:2035, 1987.                                In addition, data from GOG 33 also suggested that the
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter

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Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter

  • 1. C H A P T E R 5 Adenocarcinoma of the Uterine Corpus William T. Creasman, MD, and David Scott Miller, MD O U T L I N E Incidence 141 Tumor Grade 158 Molecular Indices 159 Epidemiology 141 Correlation of Multiple Prognostic Factors 160 Diagnosis 146 Treatment 161 Pathology 149 Surgical Management of Endometrial Cancer 161 Tumor Grade 154 Radiation Therapy 166 Prognostic Factors 154 Drug Development 168 Stage of Disease: Depth of Invasion, Cervical Special Circumstances 171 Involvement, Adnexal Involvement, and Nodal Follow-Up 173 Metastasis 155 INCIDENCE of estrogen has been implicated in the apparent increased incidence during the 1970s and early 1980s; however, In the United States, cancer of the uterine corpus is the Norway and Czechoslovakia report a 50% to 60% most common malignancy unique to women. It was esti- increase in endometrial cancer, despite the fact that mated by the American Cancer Society that uterine estrogens are rarely prescribed or are not generally avail- cancer will develop in approximately 42,160 women in able there. However, the increasing prevalence of over- 2009 in the United States, making it the fourth most weight and obesity in women, especially in developed common cancer in women. The increased incidence of countries, may account for this apparent increase. carcinoma of the endometrium has been apparent only Regardless of the reason for the increased number of during the last three decades. In reviewing the predicted women with corpus cancer, this malignant neoplasm has incidence for the 1970s, the American Cancer Society become an important factor in the care of the female noted a one and a half-fold increase in the number of patient. patients with endometrial cancer; however, there was a decline in incidence during the late 1980s. In the past several years, the incidence has remained constant. EPIDEMIOLOGY During the period of increased incidence, predicted deaths from this malignant neoplasm actually decreased Endometrial adenocarcinoma occurs during the repro- slightly. More recently, deaths from uterine cancer have ductive and menopausal years. The mean age for patients increased. In 1990 the American Cancer Society esti- with adenocarcinoma of the uterine corpus is 63 years; mated 4000 deaths from this cancer, increasing to 7780 most patients are between the ages of 50 and 59 years in 2009. An estimation of the most common new cancers (Figure 5-2). Approximately 5% of women will have and the percentage of female deaths for 2009 in the adenocarcinoma before the age of 40 years, and 20% to United States is shown in Figure 5-1. The increased use 25% will be diagnosed before menopause. Bokhman 141
  • 2. 142 5.  Adenocarcinoma of the Uterine Corpus Cervix Deaths New cases Ovary Leukemia Uterine Colorectal Lung Breast 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000 200,000 220,000 FIGURE 5-1  Common new cancer cases and deaths in women for 2010 in the United States. (Modified from American Cancer Society. Cancer Facts and Figures 2010. Atlanta. American Cancer Society, 2010.) 3500 clearly defined. Bokhman’s data suggest that patients Surgical with the first pathogenic type mainly have well- 3000 Clinical differentiated or moderately differentiated tumor, super- ficial invasion of the myometrium, high sensitivity to 2500 progestins, and favorable prognosis (85% 5-year sur- vival in his material). The patients who fall into the Number of patients second pathogenic group tend to have poorly differenti- 2000 ated tumors, deep myometrial invasion, high frequency of metastatic disease in the lymph nodes, decreased sen- 1500 sitivity to progestin, and poor prognosis (58% 5-year survival rate). 1000 Multiple risk factors for endometrial cancer have been identified, and MacMahon divides these into three categories: 500 • Variants of normal anatomy or physiology 0 • Frank abnormality or disease 15-29 30-39 40-49 50-59 60-69 70-79 80+ Age group • Exposure to external carcinogens FIGURE 5-2  Carcinoma of the corpus uteri; patients treated in Obesity, nulliparity, and late menopause are variants 1999–2001. Age distribution by mode of staging. (Modified from Creas- of normal anatomy or physiology classically associated man WT et al: Int J Gynecol Obstet 95(1):S105-143, 2006) with endometrial carcinoma. These three factors are evaluated in regard to the possible risk of developing endometrial cancer in Table 5-1. If a patient is nullipa- rous and obese and reaches menopause at age 52 years or older, she appears to have a fivefold increase in the suggested that there are two pathogenic types of endo- risk of endometrial cancer above that of the patient who metrial cancer. The first type arises in women with does not satisfy these criteria (Table 5-2). obesity, hyperlipidemia, and signs of hyperestrogenism, The type of obesity in patients with endometrial such as anovulatory uterine bleeding, infertility, late cancer has been evaluated. In a study from the Univer- onset of menopause, and hyperplasia of the stroma of sity of South Florida, it was noted that women with the ovaries and endometrium. The second pathogenic endometrial cancer had greater waist-to-hip circumfer- type of disease arises in women who have none of these ence ratios, abdomen-to-thigh skin ratios, and suprailiac- disease states or in whom the disease states are not to-thigh skin ratios than those of matched-control
  • 3. 5.  Adenocarcinoma of the Uterine Corpus 143 TABLE 5-1  Endometrial Cancer Risk Factors of consumption of most types of meats, eggs, beans, added fats, and sugar. Conversely, significant protection Risk Factors Risk was noted with an elevated intake of most vegetables, Obesity 2.5-4.5× fresh fruits, whole grain bread, and pasta. This reflected Nulliparity a low risk with increased intake of ascorbic acid and   Compared with 1 child 2×   Compared with 5 or more children beta-carotene. Of dietary interest is that the intake of 3× Late menopause 2.4× olive oil seemed beneficial in Switzerland but resembled other added fats in the Italian women. It has been previ- ously noted that the amount and type of dietary fat influence estrogen metabolism because estrogen reab- TABLE 5-2 Multiple Risk Factors sorption from the bowel seems to be increased by diets Risk rich in beef or fats. Diabetes mellitus and hypertension are frequently Nulliparous Parous associated with endometrial cancer. Elwood and col- Top 15% in weight Menopause at 52 years  5× more than  Lower two thirds in weight Menopause at <49 years leagues reported a RR of 2.8 associated with a history of diabetes after controlling for age, body weight, and socioeconomic status. High levels of insulin-like growth factor I, coupled with elevated estrogen levels, are thought to have neoplastic potential that accounts for women. As these ratios increased, the relative risk (RR) the observed increased risk of endometrial cancer. High of endometrial cancer increased. The researchers con- blood pressure is prevalent in elderly obese patients but cluded that upper-body fat localization is a significant does not appear to be a significant factor by itself, even risk factor for endometrial cancer. In a large multicenter though 25% of patients with endometrial cancer have case-control study of 403 endometrial cancer cases and hypertension or arteriosclerotic heart disease. 297 control cases, Swanson and associates confirmed As extensively detailed in Chapter 4, the relationship and amplified these findings. Women whose weight of unopposed estrogen and endometrial cancer is well exceeded 78 kg had a risk 2.3 times that of women documented. Fortunately, the addition of a progestin weighing less than 58 kg. For women weighing more appears to be protective. Adequacy of progesterone is than 96 kg, the RR increased to 4.3. Upper-body obesity important in prevention of endometrial cancer. In a (waist-to-height ratio) was a risk factor independent of study from Sweden, at the end of 5 years excess risk of body weight. Patients in the highest quartile of both endometrial cancer was 6.6 but with combined estrogen weight and waist-to-thigh circumference had a risk of progestin (E + P), RR was 1.6 for 11 to 15 days of proges- 5.8 times. The amount of body fat has been associated tin, 2.9 for 10 days of use, and 0.2 if continuous E + P with decreased circulating levels of both progesterone was given. The Million Women study from the United and sex hormone-binding proteins. There was a strong Kingdom has recently reported their findings of endo- inverse association between sitting height and risk of metrial cancer and hormone replacement therapy (HRT). endometrial cancer. This may be related to sex hormone- This study, which first reported on HRT and breast bound globulin (SHBG), which appears to be depressed cancer, has been severely criticized mainly on methodol- in women with endometrial cancer. The level of SHBG ogy factors. They had an average follow-up of 3.4 years, is progressively depressed with increasing upper-body during which 1320 incident endometrial cancers were fat localization. With lower SHBG, there is a higher diagnosed. At time of recruitment 22% of HRT users endogenous production of non–protein-bound estradiol. (total number was 320,953 women) last used continuous Because endometrial cancer is related to obesity, dietary combined therapy, 45% last used cyclic combined habits appear to be important. Data suggest that the therapy with progestogen usually added for 10 to 14 levels of estriol, total estrogens, and prolactin were lower days per month, 19% last used tibolone, and 4% used and those of SHBG were higher in postmenopausal estrogen alone. Compared with nonusers, RR of endo- women who were vegetarians. In a case-control study, metrial cancer was 0.71%, CI 0.56 to 0.90, P = 0.005; 1.05, Levi and colleagues evaluated dietary factors in 274 CI 0.91 to 1.22; 1.79, CI 1.43 to 2.25, P <0.001; and 1.45, patients with endometrial cancer and 572 control sub- CI 1.02 to 2.06, P = 0.04, respectively. Of note, the adverse jects from two areas in Switzerland and northern Italy. effects of tibolone and estrogen only were greatest in the Extensive dietary history was obtained. Their data con- nonobese woman and the beneficial effects of combined firmed the relationship between obesity and endome- HRT were greatest in obese women. Although the risk trial cancer. In relation to diet, they noted an increased of unopposed estrogen is present, women taking estro- association with total energy intake. After correction for gen who develop endometrial cancer appear to have total energy intake, a risk was present with the frequency favorable prognostic factors. Several but not all studies
  • 4. 144 5.  Adenocarcinoma of the Uterine Corpus suggest that risk factors such as multiparity and obesity differences are unexplained. An analysis of the Gyneco- are lower in the estrogen users. Stage of disease and logic Oncology Group (GOG) database evaluated this histologic grade appear to be lower in estrogen users. factor in 600 white and 91 black women with clinical With correction for stage and grade, estrogen users still stage I or stage II endometrial cancer. A larger number have less myometrial invasion than nonestrogen users of the African American women were diagnosed after do. The poor prognostic subtypes, such as clear cell car- age 70 years, and they had a higher proportion of papil- cinoma and adenosquamous cancer, appear less fre- lary serous (PS) and clear cell histologic types; the black quently in estrogen users. As a result, survival rates with women also had more advanced disease, grade, vascular estrogen-related endometrial cancer are much better space involvement, depth of invasion, and lymph node than those of nonestrogen cancers. In fact, some studies metastases than the white women did. Survival (5-year) note just as good if not better survival in estrogen users was 77% for white women and 60% for black women. than in women with nonestrogen, nonendometrial Survival difference remained even in high-risk groups cancers. such as grade III tumors (59% vs 37%, respectively). The Data indicate that the use of combination oral contra- unadjusted hazard rate was 2.0, which was statistically ceptives decreases the risk for development of endome- significant. With adjustment for age, cell type, and extent trial cancer. The Centers for Disease Control and of disease, the RR dropped to 1.2. The adjusted risk rate Prevention evaluated endometrial cancer cases of all suggests that race is not a significant factor; nevertheless, women aged 20 to 54 years from eight population-based race does denote an increased risk for poor prognostic cancer registries and compared them with control factors, which clinically may be important. patients selected at random from the same centers. A Tamoxifen is used to prevent or treat breast cancer. comparison of the first 187 cases with 1320 control cases Tamoxifen was first introduced in clinical trials in the showed that women who used oral contraceptives at early 1970s and was approved in 1978 by the U.S. Food some time had a 0.5 RR of developing endometrial and Drug Administration (FDA) for treatment of cancer compared with women who had never used oral advanced breast carcinoma in postmenopausal woman. contraceptives. This protection occurred in women who Tamoxifen, although labeled an antiestrogen, is known used oral contraceptives for at least 12 months, and pro- to have estrogenic properties and truly is a weak estro- tection continued for at least 10 years after oral contra- gen. Women receiving tamoxifen also appear to have ceptive use. Protection was most notable for nulliparous some protection from osteoporosis and heart disease women. These investigators estimated that about 2000 (decreased lactate dehydrogenase and cholesterol), cases of endometrial cancer are prevented each year in much like women receiving estrogen replacement the United States by past or current use of oral contra- therapy. Extensive experience with this drug has been ceptives. Of interest, cigarette smoking appears to reported. It is estimated that more than 4 million women decrease the risk for developing endometrial cancer. In in the United States have taken tamoxifen for almost 8 a population-based case-control study of women aged million women-years of use. One of its major benefits is 40 to 60 years, Lawrence and associates found a signifi- that in women taking tamoxifen, there has been a sub- cant decline in RR of endometrial carcinoma with stantial decrease in the incidence of a second cancer in increased smoking (P >0.05). The RR decreased by about the opposite breast compared with similar women who 30% when one pack of cigarettes was smoked per day were taking a placebo. and by another 30% when more than one pack was The Early Breast Cancer Trialists Collaborative Group smoked per day. The effects of smoking did not appear (EBCTCG) has produced an important meta-analysis of to vary with menstrual status or exogenous estrogen. 194 randomized trials of adjuvant chemotherapy or There was a fourfold increase in smoking-related odds endocrine therapy with at least 15 years of follow-up. ratio with body weight; the greatest reduction in risk by The analysis evaluated the effects of adjuvant tamoxifen smoking was in the heaviest women. However, the esti- on breast cancer recurrence and survival. It was shown mated risk increased twelvefold in overweight women that 5 years of tamoxifen therapy, compared to no adju- who were nonsmokers and whose primary source of vant therapy, reduced the 15-year probability of breast estrogen was peripheral conversion of androgen to cancer recurrence (from 45% to 33%) and breast cancer estrogen. Although smoking apparently reduces the risk mortality (from 35% to 26%). In addition, tamoxifen has for development of early-stage endometrial cancer, this been shown to provide a preventive benefit in women advantage is strongly outweighed by the increased risk at risk for developing breast cancer. of lung cancer and other major health hazards associated There has been a considerable amount of discussion with cigarette smoking. in the literature in regard to the association of tamoxifen Incidence and survival are higher in white women with endometrial cancer. At least three studies (Fisher compared with black women. Reasons for these and colleagues, Powels and colleagues, and Veronesi
  • 5. 5.  Adenocarcinoma of the Uterine Corpus 145 and colleagues) evaluating the prophylactic use of the prevention of recurrences and new breast cancer in tamoxifen in women without breast cancer have reported comparison to new endometrial cancers were evaluated an association between tamoxifen use and endometrial in the NSABP study. The benefits suggest that 121 fewer cancer. In addition, several cases of endometrial cancer breast-related events per 1000 women treated with have been described in women receiving tamoxifen. In tamoxifen were seen compared with 6.3 endometrial a prospective, randomized study of the National Surgi- cancers per 1000 women. Therefore the benefit from cal Adjuvant Breast and Bowel Project (NSABP), 2843 tamoxifen is apparent. patients with node-negative estrogen receptor–positive It was initially suggested that the rate of endometrial invasive breast cancer were randomly assigned to receive cancers associated with tamoxifen might be equal to a placebo or 20 mg/day of tamoxifen. An additional that associated with unopposed estrogen replacement 1220 tamoxifen-treated patients were registered and therapy. Because tamoxifen is a weak estrogen, similar given the drug. The average time in the study was 8 characteristics of endometrial cancer were also implied years for the randomly assigned patients and 5 years for (i.e., well-differentiated superficially invasive cancers). the registered patients. Of the 1419 patients randomly Barakat and associates reviewed five studies, including assigned to tamoxifen, 15 developed uterine cancer, of the study by Magriples, the NSABP, their own data from which two were sarcomas. One patient randomly Memorial Sloan-Kettering Hospital, and two studies assigned to receive tamoxifen did not take the drug and from overseas. A total of 103 patients were evaluated in developed endometrial cancer 78 months after random- regard to histologic features, grade of tumor, Interna- ization. In the placebo group, two developed endome- tional Federation of Gynecology and Obstetrics (FIGO) trial cancer; however, both were receiving tamoxifen at staging, and deaths from uterine cancer; an increase was the time of their uterine malignant disease. One patient not found in poor prognostic histologic findings, tumor had a breast recurrence and was prescribed tamoxifen, differentiation, or stage compared with what would be and the other was given tamoxifen after colon cancer. expected in a similar group of non–tamoxifen-treated Two of the patients with endometrial cancer had been patients with uterine cancer. Jordan, in an evaluation of taking tamoxifen for only 5 and 8 months before their the SEER data and of tamoxifen-associated endometrial diagnosis of uterine disease was made. Five patients cancer in the literature, reported similar findings. in the tamoxifen group developed endometrial cancer It is suggested that all women, irrespective of whether after the drug had been discontinued for 7 to 73 months. they are taking tamoxifen, should have yearly gyneco- In the registered patients who received tamoxifen, eight logic examinations. The endometrium should be evalu- uterine tumors (seven endometrial) were subsequently ated if the patient is symptomatic. We do not currently diagnosed. Three of these patients had been taking recommend endometrial sampling or ultrasound evalu- tamoxifen for less than a year (2 months, 2 months, and ation of the endometrium just because an individual is 9 months). The authors determined the average annual taking tamoxifen. This possible concern of tamoxifen hazard rate of endometrial cancer per 1000 women in and endometrial cancer may lessen in the near future their population of patients. This was 0.2 per 1000 in the because the aromatase inhibitors (AIs) may appear to be placebo group and 1.6 per 1000 for the randomized better than tamoxifen in the prevention of recurrent or tamoxifen-treated patients. In the registered patients contralateral breast cancer. Several clinical trials have receiving tamoxifen, the average annual hazard rate was demonstrated the comparable if not greater efficacy 1.4 per 1000, similar to that of the randomized tamoxifen- of AIs compared to tamoxifen. Although tamoxifen treated group. The hazard rate of endometrial cancer in remains an option for adjuvant therapy for postmeno- the placebo group was low compared with the Surveil- pausal women, AIs are thought to be more effective lance, Epidemiology, and End Results (SEER) data and in preventing breast cancer recurrence in the first 2 with previous NSABP randomized tamoxifen–placebo years after surgery. AIs reduce estrogen levels in studies; these data suggest that the average annual postmenopausal women by inhibiting or inactivating hazard rate is 0.7 per 1000. aromatase, the enzyme that synthesize estrogens These data, based on a limited number of patients from circulating androgens. AIs should be avoided in with endometrial cancer while receiving tamoxifen, premenopausal women, including those who have expe- suggest that there may be a RR of 2.3 for development rienced chemotherapy-induced amenorrhea. Whereas of endometrial cancer while receiving tamoxifen. This tamoxifen is a partial agonist, AIs are not agonists and does not take into account the well-known fact that are not associated with estrogenic-related thromboem- women who develop breast cancer are at an increased bolic events and uterine cancers. The activity of third- risk for development of endometrial cancer irrespective generation agents anastrozole, letrozole, and exemestane of subsequent treatment. The RR of 1.72 to more than is generally considered comparable. Although AIs 3 has been reported. The risks and benefits of are associated with a significant risk of osteoporosis,
  • 6. 146 5.  Adenocarcinoma of the Uterine Corpus they do not increase the risk of gynecologic problems. In ovaries has been shown to decrease the risk of uterine one large adjuvant therapy trial (the Anastrozole, and ovarian cancer in these high-risk patients. Tamoxifen Alone or in Combination Trial [ATAC]), anas- trozole was associated with fewer cerebrovascular events (2.0% vs 2.8%), endometrial cancers (0.2% vs 0.8%) DIAGNOSIS thromboembolism (2.8% vs 4.5%), hot flashes (41% vs 36%), and vaginal bleeding (5.4% vs 10.2%) compared Routine screening for uterine adenocarcinoma and its with tamoxifen. The role of AIs as prophylaxis is precursors is not recommended. Women receiving HRT being investigated, but data are lacking at the present (estrogen and progesterone) do not need endometrial time. biopsy before institution of therapy or during replace- Although most cases of endometrial cancer are spo- ment therapy unless abnormal bleeding occurs. Monthly radic, hereditary endometrial cancer has been identified withdrawal bleeding after progestin is not considered in association with hereditary nonpolyposis colon abnormal bleeding. However, breakthrough bleeding cancer (HNPCC), also known as Lynch II syndrome. should be evaluated. The use of continuous estrogen This is an autosomal-dominant inherited cancer that alone increases the risk of adenocarcinoma. Estrogen involves a germline mutation in one of the genes in the plus progesterone appears to decrease the risk of adeno- DNA mismatch repair gene family, which includes carcinoma and therefore is the preferred treatment. In MSH2, MLM1, and MSH6. Fortunately, HNPCC asymptomatic high-risk patients, periodic screening accounts for only 1% to 5% of all colorectal cancers, but may be advisable. All postmenopausal women with it is associated with a 39% to 54% lifetime risk of devel- uterine bleeding must be evaluated for endometrial oping colon cancer. There is a lifetime risk of 30% to cancer, although only 20% of these patients will have a 61% of developing endometrial cancer. There is also an malignant genital neoplasm. As the patient’s age increased risk of ovarian cancers and other nongyneco- increases after menopause, there is a progressively logic cancers. In a study by Lu and associates, they increasing probability that her uterine bleeding is caused noted that about half the time, the endometrial or by endometrial cancer. Feldman and associates found ovarian cancer appeared before the colon cancer. In both that age was the greatest independent risk factor associ- instances, the age at diagnosis was in the early 40s. ated with endometrial cancer or complex hyperplasia. In There was a median of 11 years between the gynecologic women aged 70 years or older, the odds ratio was 9.1. If cancer and the colon cancer. About 14% of the time the complex hyperplasia was present, the odds ratio gynecologic and colon cancers were diagnosed simulta- increased to 16. When a woman was older than 70 years, neously. Several “red flags” should prompt an evalua- her chance of having cancer when vaginal bleeding was tion for HNPCC. These include any individual with a present was about 50%. If she was also nulliparous personal or family history of colon cancer at an early and had diabetes, the risk was 87%. A perimenopausal age of onset (usually before age 50) or endometrial patient who may have abnormal uterine bleeding indic- cancer at an early age of onset (premenopausal or before ative of endometrial cancer is frequently not evaluated age 50) and two or more HNPCC-related cancers in an because the patient or her physician interprets her new individual or family. Assessing a patient’s risk for bleeding pattern as resulting from menopause. During hereditary cancer is an important process, beginning this time in a woman’s life, the menstrual periods should with screening for the “red flags” of hereditary colon become lighter and lighter and farther and farther apart. (and endometrial) cancer. Individuals with any of the Any other bleeding pattern should be evaluated with “red flags” should enter into a discussion about genetic carcinoma of the endometrium in mind. A high index of testing to determine if this is appropriate for them. suspicion must be maintained if the diagnosis of endo- Medical management strategies can be tailored depend- metrial cancer is to be made in the young patient. Pro- ing on the genetic testing results and may include longed and heavy menstrual periods and intermenstrual increased surveillance, chemoprevention, and prophy- spotting may indicate cancer, and endometrial sampling lactic surgery. The Cancer Study Consortium suggests is advised. Most young patients who develop endome- colonoscopy every 1 to 3 years beginning at age 25 in trial cancer are obese, in many instances massively over- individuals with this hereditary disorder. The data weight, often with anovulatory menstrual cycles. suggest that if surveillance is done, survival is improved. Historically, fractional dilation and curettage (D&C) Women should be offered surveillance with ultrasound has been the definitive diagnostic procedure used in and endometrial sampling from age 25 to 35, although ruling out endometrial cancer. Today, most advocate the there are no data to suggest this will improve survival routine use of the endometrial biopsy as an office proce- if endometrial cancer is diagnosed by these means. As dure to make a definitive diagnosis and spare the patient reported by Schmeler and colleagues, risk-reducing hospitalization and an anesthetic. Several studies have surgery consisting of removal of the uterus and bilateral indicated that the accuracy of the endometrial biopsy in
  • 7. 5.  Adenocarcinoma of the Uterine Corpus 147 detecting endometrial cancer is approximately 90%. 65 primary studies on the use of hysteroscopy to diag- Cytologic detection of endometrial cancer by routine nose endometrial cancer and endometrial disease (can­ cervical Papanicolaou (Pap) smear has generally been cer, hyperplasia, or both), including more than 26,000 poor in comparison with the efficacy of the Pap smear women. All of the patients had abnormal premeno- in diagnosing early cervical disease. Several studies in pausal or postmenopausal uterine bleeding. Using endo- the literature indicate that only one third to half of the metrial histologic findings as a reference, a positive patients with adenocarcinoma of the endometrium have hysteroscopy result was associated with a 72% probabil- abnormal Pap smears on routine cervical screening. The ity of endometrial cancer, whereas a negative result main reason for the poor detection with the cervical Pap reduced this probability to 0.6%. The corresponding smear is that cells are not removed directly from the probabilities for endometrial disease were 55% with a lesion as they are on the cervix. When a cytologic prepa- positive result and 3% with a negative result. The accu- ration is obtained directly from the endometrial cavity, racy of hysteroscopy tended to be higher among post- malignant cells are present in higher numbers than those menopausal women and in an outpatient setting. They found if routine cervical or vaginal smears are obtained. concluded that hysteroscopy is highly accurate and Techniques that obtain only a cytologic preparation are thereby clinically useful in diagnosing endometrial generally inadequate if they are used alone. cancer in women with abnormal uterine bleeding and is Several commercial apparatuses are available for moderately useful in diagnosing endometrial disease. sampling the endometrial cavity on an outpatient basis. Because many patients with endometrial cancer can be If diagnosis of endometrial cancer can be made on an diagnosed with office biopsy, that is our preferred first outpatient basis, the patient can avoid hospitalization diagnostic step. If the biopsy result is negative and and a minor surgical procedure. Devices that remove further evaluation is needed, we proceed to hysteros- tissue for histologic evaluation have generally been good copy. With its use, surgeons can direct biopsies of focal if tissue is obtained from the endometrial cavity. Stovall lesions that might be missed by D&C. Hysteroscopy can and colleagues evaluated 40 patients known to have also be used to evaluate the endocervical canal. endometrial cancer with the Pipelle instrument. Ninety Ultrasonography (US) has been suggested as a diag- percent of the women were postmenopausal. Only in nostic tool in evaluating women with irregular bleeding, one patient was cancer not identified with the Pipelle. particularly the postmenopausal patient (Figure 5-3). This patient had a prior D&C that revealed a grade I The endometrial stripe as seen with transvaginal US lesion. The Pipelle diagnosis was atypical adenomatous appears to be indicative of endometrial thickness. Several hyperplasia, and the hysterectomy specimen revealed a studies suggest that if a thin endometrial stripe is present, focus of adenocarcinoma in situ. The pathologist noted a histologic diagnosis is not necessary because atrophic that the obtainable tissue was acceptable for analysis in endometrium would be present. Granberg and associ- 100% of patients. Discomfort was recorded as mild in ates evaluated 205 women with postmenopausal bleed- 80%, and only two patients (5%) reported severe pain. ing, 30 postmenopausal asymptomatic women, and 30 Goldchmit and coworkers reported similar accuracy postmenopausal patients with known endometrial with the Pipelle in 176 consecutive patients undergoing cancer. In the two groups of 60 patients, the endometrial D&C. Whereas endometrial biopsy and D&C appear to thickness was 3.2 (mean) versus 17.7, respectively. In the be equivalent in terms of diagnosing cancer, the accuracy group of 205 women, 18 were found to have endometrial of endometrial biopsy appears to be inferior to D&C in cancer. No cancers were present in the endometrium that predicting final posthysterectomy tumor grade. In a had an endometrial thickness of 8 mm or less. There was recent study by Leitao and colleagues, 18% of endome- considerable overlap of endometrial thickness by all trial biopsy specimens were upgraded on final hysterec- histologic groups. The authors noted that if a cutoff of tomy specimen, whereas only 9% of D&C specimens 5 mm was used, no false-negative findings were present. were upgraded. In the symptomatic patient in whom With this measurement, the positive predictive value inadequate tissue (or no tissue at all) is obtained for was 87%, with specificity of 96% and sensitivity of 100% pathologic evaluation, a D&C must be considered. for identifying endometrial abnormalities. It has been Hysteroscopy has been suggested as adjuvant in suggested that if US could save a large number of endo- making the diagnosis of endometrial cancer and in metrial biopsies, there would be a large cost savings establishing the extent of disease. Hysteroscopy has with less discomfort to the patient. As previously noted, been used frequently in the evaluation of patients with significant pain with the newer disposable endometrial abnormal uterine bleeding and has the advantages of biopsy techniques affects only a small number of patients; allowing the physician to see the pathologic lesion and and a certain number of patients, because of consider- direct biopsy, identify other competing diagnoses able endometrial thickness, will require endometrial (fibroids, polyps), and perform the procedure on an out- sampling anyway. Clark and colleagues investigated patient basis. Clark and colleagues analyzed data from the cost-effectiveness of initial diagnostic strategies for
  • 8. 148 5.  Adenocarcinoma of the Uterine Corpus A B C FIGURE 5-3  A, Ultrasound of the uterus showing the “triple line” indicating the thickness of the endometrium. B, Ultrasound of the uterus showing a “thickened endometrium” of more than 10 mm. C, Saline instillation of the endometrial cavity notes a well-defined submucous fibroid and not thickened endometrium. postmenopausal bleeding. A decision analytic model reviews, clinical outcomes from published literature and was constructed to reflect current service provision, cost estimates from local and National Health Service which evaluated 12 diagnostic strategies using endome- sources. The main outcome measure was the cost per trial biopsy, ultrasonography (4- and 5-mm endometrial additional life year gained (£/LYG). Compared with car- thickness cutoff), and hysteroscopy. Diagnostic probabil- rying out no initial investigation, a strategy based on ity estimates were derived from systematic quantitative initial diagnosis with US using a 5-mm cutoff was the
  • 9. 5.  Adenocarcinoma of the Uterine Corpus 149 least expensive (£11 470/LYG). Initial investigation with endometrial thickness on US of 5 mm or more versus endometrial biopsy or US using a 4-mm cutoff was com- 19% in the non-tamoxifen group (51% vs 8% more than parably cost-effective (<£30 000/LYG vs US with a 5-mm 10 mm, respectively). Hysteroscopy findings noted that cutoff). The strategies involving initial evaluation with 28% of uterine mucosa was atrophic versus 87% in the test combinations or hysteroscopy alone were not cost- non-tamoxifen control group. Histopathologic examina- effective. They concluded that women presenting for the tion noted atrophic endometrium in 60% of tamoxifen- first time with postmenopausal bleeding should undergo treated patients versus 79% of control subjects. The initial evaluation with US or endometrial biopsy. biggest difference between the two groups was the Unfortunately, endometrial cancer has been identified finding of polyps in 18% of the tamoxifen group versus when the endometrial thickness is less than 5 mm. 0% of the control group; this appears to be a frequent Although studies may evaluate several hundred patients, finding in the tamoxifen-treated patient. So-called mega- most do not have many cancer patients included. Wang polyps measuring up to 12 cm have been described. and associates reviewed the ultrasound of 52 women Other uterine disease has been attributed to tamoxifen, who were diagnosed with papillary serous clear cell and including increased uterine volume, lower impedance to other high-grade carcinomas. Of the 52, 34 (65%) had blood flow in uterine arteries, endometriosis, focal peri- thickened endometrium measuring 5 mm or more; in 9 glandular condensation of stromal cells, and epithelial (17%) the endometrium was less tham 5 mm, and in an metaplasia. Data now suggest that the markedly thick- additional 9 women (17%) the endometrium was indis- ened endometrium (up to 40 mm) in patients receiving tinct. In the women with nonthickened endometrium, tamoxifen is not thickened endometrium but proximal other ultrasound abnormalities were noted: intracavi- myometrium. tary fluid or lesion, myometrial mass, enlarged uterus, US has also been evaluated as a means for determin- or adnexal mass. Multiple factors can affect endometrial ing depth of myometrial invasion. Gordon and associ- thickness. These include estrogen, estrogen plus proges- ates studied 15 known patients with endometrial cancer tin, body mass index (BMI), diabetes, poor histotype, by US and magnetic resonance imaging (MRI). By use of race, and postmenopausal status. The Committee on criteria of greater than 50% myometrial wall involve- Gynecologic Practice of the American College of Obste- ment as deep invasion and less than 50% as superficial tricians and Gynecologists issued an opinion on the role invasion, US was judged to be more accurate than MRI of transvaginal ultrasonography in the evaluation of in five studies; MRI was better in three, both were equally postmenopausal bleeding. They concluded that women accurate in four, and neither was accurate in three. It has with postmenopausal bleeding may be assessed initially been suggested by some that US can accurately predict with either endometrial biopsy or transvaginal ultraso- myometrial invasion in about 75% of cases. Although nography. This initial evaluation does not require per- knowing the depth of invasion preoperatively would be formance of both tests. Transvaginal ultrasonography important information to the clinician, the data from can be useful in the triage of patients in whom endome- studies as noted before would currently appear to be too trial sampling was performed but tissue was insufficient premature or too costly to use routinely. We prefer to for diagnosis. When transvaginal ultrasonography is evaluate depth of myometrial invasion intraoperatively performed for patients with postmenopausal bleeding with gross examination or frozen section. and an endometrial thickness of less than or equal to 4 mm is found, endometrial sampling is not required. Pathology Meaningful assessment of the endometrium by ultraso- nography is not possible in all patients. In such cases, Careful evaluation of the uterus by the pathologist is alternative assessment should be completed. When essential for proper diagnosis and treatment of corpus bleeding persists despite negative initial evaluations, cancer (Figure 5-4). Gross inspection of a bivalved uterus additional assessment is indicated. at the time of hysterectomy can offer an impression of The reliability determining endometrial thickness in the size of the lesion, its location (involvement of fundus, the postmenopausal patient does not appear to be appli- lower uterine segment, or cervix), and depth of tumor cable to women taking tamoxifen. In all studies, the penetration into the myometrium (depth of invasion). A endometrium in the tamoxifen-treated patient is consid- clinically enlarged uterus may be caused by increasing erably thicker than in the non–tamoxifen-treated patient. tumor volume, but this should not be the only gauge for Histologic evaluation revealed atrophic endometrium significant local disease. Obviously, many patients can in a large number of these tamoxifen-treated patients. have enlarged uteri because of factors other than adeno- Lahti and colleagues evaluated 103 asymptomatic post- carcinoma. Carcinoma of the endometrium may start as menopausal patients (51 receiving tamoxifen and 52 a focal discrete lesion, as in an endometrial polyp. It may control subjects) with US, hysteroscopy, and endometrial also be diffuse in several different areas, in some situa- histologic examination. In the tamoxifen group, 84% had tions involving the entire endometrial surface. As the
  • 10. 150 5.  Adenocarcinoma of the Uterine Corpus TABLE 5-3  Endometrial Carcinoma Subtypes Type Number (%) 11 12 Endometrioid 6231 (84) 13 Adenosquamous 317 (4.2) 5 14 Mucinous 74 (0.9) 4 Papillary serous 335 (4.5) Clear cell 185 (2.5) 3 Squamous cell 28 (0.04) Other 285 (3.8) 2 10 From Pecorelli S (ed): Int J Gynecol Obstet 83:79, 2003. 1 9 8 7 6 of patients. Historically, patients with a squamous com- ponent were further stratified according to whether the squamous component appeared benign (designated adenoacanthoma, AA) or malignant (designated adeno- squamous carcinoma, AS). It was suggested that AA indicated a good prognosis, and those with AS had a poor survival. Today, this distinction has been ques- FIGURE 5-4  Pathologic evaluation of endometrial cancer. (Courtesy tioned in regard to its prognostic importance. Zaino and Paul Underwood, MD.) co-workers, in reporting data from the GOG, suggest that the notation of squamous component irrespective of differentiation does not affect survival. Patients with tumor grows, it can become larger and/or spread within clinical stage I and stage II cancers were evaluated, and the endometrium or myometrium. Endometrial cancer 456 with typical adenocarcinoma (AC) and 175 with may disseminate to regional lymph nodes, by emboliza- squamous differentiation (AC + SQ) were identified. The tion or direct extension into the pelvis or vagina, or latter were subdivided into 99 with AA and 69 with AS. hematogenously to distant organs (Figure 5-5). The risk Multiple known prognostic factors were compared with of spread is related to several factors, including depth of differentiation of glandular and squamous component invasion into the myometrium, tumor grade, and histo- of the tumor. Age, depth of myometrial invasion, archi- logic type. tecture, nuclear grade, and combined grade were similar Adenocarcinoma, the most common histologic type, for AC and AC + SQ, although patients with AA were is usually preceded by a predisposing lesion, atypical better differentiated than those with AS and had less endometrial hyperplasia (Table 5-3). Only those hyper- myometrial invasion. Both glandular and squamous dif- plasias with cellular atypia are considered to be precur- ferentiation correlated with frequency of pelvic and sors of adenocarcinoma of the endometrium. For most para-aortic node metastasis. Nodal metastasis, when it patients with endometrioid-type tumors, particularly was stratified for grade and depth of invasion, was grade I-II lesions, and hyperplasia, hyperestrogenism is similar in AC and AC + SQ patients. The differentiation the etiologic basis. Pathologically, endometrial cancer is of squamous component is closely correlated with the characterized by the presence of glands in an abnormal differentiation of the glandular element, and the glandu- relationship to each other, with the hallmark of little if lar element is a better predictor of outcome. It would any intervening stroma between the glands. There can therefore appear that the previous designation of AA be variations in the size of the glands, and infolding is and AS has no added predictive property than differen- common. The cells are usually enlarged, as are the nuclei, tiation of glandular component and probably should along with nuclear chromatin clumping and nucleolar be dropped as a diagnostic term. The authors suggest enlargement. Mitosis may be frequent. Differentiation of the term squamous differentiation instead, with differ- adenocarcinoma (mild, moderate, and severe, or grades entiation of the glandular component noted as the I-III) is important prognostically and is incorporated into important prognostic factor. Subsequently, Abeler and FIGO surgical staging (Figure 5-6). Most studies suggest Kjorstad reviewed 255 cases and made the same that 60% to 65% of all endometrial cancers are of this recommendations. subtype. Secretory adenocarcinoma (Figure 5-7) is an uncom- For almost a century, it has been recognized that a mon type of endometrial cancer. It usually represents squamous component may be associated with an adeno- well-differentiated carcinoma with progestational carcinoma of the endometrium. This occurs in about 25% changes. It is difficult to differentiate it from secretory
  • 11. 5.  Adenocarcinoma of the Uterine Corpus 151 Endometrium Stage Ia Endocervical Stage Ib Stage Ic glands Myometrium Stage IIb Stage IIa Stage IIb Stage IIa Endocervical stroma Endocervical canal Stage Ia: Tumor limited to endometrium Stage IIa: Endocervical glandular involvement only Stage Ib: Invasion to less than half the myometrium Stage IIb: Cervical stroma invasion Stage Ic: Invasion to more than half the myometrium Stage I Stage II Pelvic Periaortic nodes nodes Positive cytology Stage IIIA Stage IIIB Stage IIIC Omentum Inguinal nodes Stage IVa Stage IVb
  • 12. 152 5.  Adenocarcinoma of the Uterine Corpus Pelvic Organs Lymph Nodes Aortics Common iliacs Loose cancer cells Hypogastrics in peritoneal cavity External iliacs Small bowel implants Involved ovary Extension to broad ligament Obturator Vaginal Inguinals Paracervical FIGURE 5-5  Spread pattern of endometrial cancer with particular emphasis on potential lymph node spread. Pelvic and periaortic nodes are at risk, even in stage I disease. endometrium. Survival is good and comparable to that that has a propensity for vascular or lymphatic vascular associated with the pure adenocarcinoma. Although it is space involvement (LVSI). Well-formed papillae are an interesting histologic variant, the separation of the lined by neoplastic cells with grade III cytologic features entity as it relates to treatment and survival is probably (Figure 5-8). Differentiation between papillary architec- not warranted. ture and syncytial metaplasia with benign endometrial Increasing emphasis has been placed on the impor- alterations must be made because the papillary architec- tance of the histologic subtype serous adenocarcinoma ture alone does not designate PS. The uterus may appear (SC) of the uterus (also called uterine papillary serous grossly normal but can have extensive myometrial inva- carcinoma, UPSC). This subtype represents less than sion. Most UPSC tumors are aneuploid and have a 10% of all adenocarcinomas but is a highly aggressive high S-phase. Serous cancers can be pure or admixed carcinoma of the uterus. Unlike the more common vari- with other histologic types (endometrioid, clear cell, ants, PS is not associated with hyperestrogenism and carcinosarcoma). frequently develops in the setting of atrophic endome- Clear cell carcinomas (Figure 5-9) are also infrequent trium. It is more commonly seen in older and nonwhite in number but have distinct histologic criteria. Clear cell patients. Hendrickson, in the early 1980s, noted that in tumors are characterized by large polyhedral epithelial more than 250 endometrial cancers, only 10% had histo- cells that may be admixed with typical non–clear logic features of SC, but these accounted for 50% of cell adenocarcinomas. Some authorities accept the all treatment failures. The histopathologic appearance mesonephritic-type hobnail cells as part of this pattern, resembles a high-grade serous carcinoma of the ovary whereas others believe that this histologic type should
  • 13. 5.  Adenocarcinoma of the Uterine Corpus 153 A FIGURE 5-7  High-power view of well-differentiated secretory car- cinoma invading inner one-third of the myometrium. (Courtesy William M. Christopherson, MD, Louisville, Kentucky.) B FIGURE 5-8  Serous adenocarcinoma. Similarity to ovarian carci- noma is apparent. (Courtesy Gregory Spiegel, MD.) C FIGURE 5-6  Histologic patterns of differentiation in endometrial carcinoma. A, Well-differentiated (G1). B, Moderately differentiated (G2). C, Poorly differentiated (G3). (Courtesy Gregory Spiegel, MD.) FIGURE 5-9  Clear cell carcinoma of the endometrium. Clear cell component is quite evident. (Courtesy Gregory Spiegel, MD.)
  • 14. 154 5.  Adenocarcinoma of the Uterine Corpus be excluded from the clear cell category. Silverberg and grade, raises the grade of a grade I or grade II tumor by DeGiorgi and Kurman and Scully suggested a worse one. By convention, serous and clear tumors are consid- prognosis for clear cell adenocarcinoma than for pure ered grade III/high-grade tumors. adenocarcinoma. This was confirmed in studies by Christopherson and co-workers. Even in stage I disease, only 44% of patients with clear cell carcinomas survive PROGNOSTIC FACTORS 5 years. Neither the FIGO classification nor nuclear grade correlates with survival. Photopulos and associ- Following hysterectomy and lymph node dissection, ates, in a review of their material, noted that their patients clinical-pathologic characteristics are commonly used to with this entity were older and tended to have a worse predict risk of recurrence and to optimize therapy. Mul- prognosis. They did note that patients with stage I clear tiple factors have been identified for endometrial carci- cell carcinomas had a 5-year survival similar to that of noma that have prognostic value (Table 5-4). Essentially patients with stage I pure adenocarcinoma of the all reports in the literature agree stage (extent of disease endometrium. spread), grade of tumor, and depth of invasion are important prognostic considerations. Before 1988 endo- metrial cancer was clinically staged with stage assign- Tumor Grade ments based on uterine size and clinical extent of disease. In addition to histologic type, pathologists assign a Because of the considerable discrepancy between the measure of tumor differentiation, known as grade, to clinical extent of disease spread and pathologic spread endometrial cancers. Grade I lesions are well differenti- noted after surgical staging, FIGO adopted a surgical- ated, are frequently associated with estrogen excess, pathologic staging classification in 1988. In 2009 FIGO closely resemble hyperplastic endometrium, and are updated the staging system (Table 5-5). FIGO staging generally associated with a favorable prognosis. Grade classification attempts to categorize patients into prog- III lesions are poorly differentiated, do not resemble nostic groups based on extent of disease and tumor normal endometrium, and frequently have a poorer grade. prognosis. Grade II tumors are moderately well differ- entiated and have an intermediate prognosis. Both archi- tectural criteria and nuclear grade are used to classify. Architectural grade is related to the proportion of solid tumor growth, with grade I having an adenocarcinoma TABLE 5-4  Prognostic Factors in Endometrial Adenocarcinoma in which less than 5% of the tumor growth is in solid Histologic type (pathology) sheets, grade II has 6% to 50% of the neoplasm arranged Histologic differentiation in solid sheets of neoplastic cells, and grade III has Stage of disease greater than 50% of the neoplastic cells in solid masses. Myometrial invasion Regions of squamous differentiation are excluded from Peritoneal cytology Lymph node metastasis this assessment. The FIGO rules for grading state that Adnexal metastasis notable nuclear atypia, inappropriate for architectural TABLE 5-5  2009 FlGO Staging System for Carcinoma of the Endometrium Stage I* Tumor contained to the corpus uteri IA No or less than half myometrial invasion IB Invasion equal to or more than half of the myometrium Stage II Tumor invades the cervical stroma but does not extend beyond the uterus† Stage III* Local and/or regional spread of tumor‡ IIIA Tumor invades the serosa of the corpus uteri and/or adnexas IIIB Vaginal and/or parametrial involvement IIIC Metastases to pelvis and/or para-aortic lymph nodes IIICl Positive pelvic nodes IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph nodes Stage IV* Tumor invades bladder and/or bowel mucosa and/or distant metastases IVA Tumor invasion of bladder and/or bowel mucosa IVB Disant metastases, including intra-abdominal metastases and/or inguinal lymph nodes *Includes grades 1, 2, or 3. † Endocervical glandular involvement only should be considered as stage I and no longer as stage II. ‡ Positive cytology has to be reported separately without changing the stage.
  • 15. 5.  Adenocarcinoma of the Uterine Corpus 155 Stage of Disease: Depth of Invasion, care for patients with endometrial cancer. GOG protocol Cervical Involvement, Adnexal Involvement, 33 was a surgical-pathologic study of 621 patients with clinical stage I endometrial cancer who were uniformly and Nodal Metastasis treated with total abdominal hysterectomy, bilateral Staging of patients with malignancies is designed to salpingo-oophorectomy, peritoneal cytologic evaluation, have prognostic value by classifying the size and extent and selective pelvic and para-aortic selected lymphad- of tumor. The survival rate in regard to stage of disease enectomy. Before this study, it was presumed most has been consistent, and Table 5-6 and Figure 5-10 show patients with endometrial cancer were at risk for nodal the 5-year survival rate reported by FIGO (FIGO 1988 metastases and nearly all patients required some form staging). The patterns of disease spread in endometrial of pelvic radiation therapy (either preoperatively or cancer was evaluated in a prospective study performed postoperatively). The study demonstrated important by the GOG (GOG protocol 33) and reported by Creas- relationships between pathologic factors and risk of man. This study is required reading for physicians who nodal disease. For example, factors associated with nodal disease included higher tumor grade, deeper myometrial invasion, cervical involvement, (+) cytology, TABLE 5-6 Five-Year Survival in Endometrial Cancer: Surgical and LVSI. As a result of this study FIGO accepted a Stage surgical-based staging system of endometrial cancer in 1988. Stage No. of Patients Five-Year Survival (%) For endometrial cancer, FIGO staging reflects the pro- Ia 1063 91 gression of disease within the uterus and at extrauterine Ib 2735 90 sites. Approximately 75% of patients with endometrial Ic 1219 81 cancer present with disease limited to the uterus (Table IIa 364 79 IIb 426 71 5-7). For stage I disease, depth of tumor invasion into the IIIa 484 60 myometrium is an important prognostic factor. The IIIb 73 30 degree of myometrial invasion is a consistent indicator IIIc 293 52 of tumor virulence (Figure 5-11). DiSaia and associates IVa 47 15 noted that recurrences were directly related to depth of IVb 160 17 myometrial invasion in patients with stage I cancer From Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003. treated primarily with surgery (Table 5-8). The Annual 100 Stage Ia (n ϭ 1063) Stage Ib (n ϭ 2735) Stage Ic (n ϭ 1219) 80 Stage IIa (n ϭ 364) Stage IIb (n ϭ 426) Proportion surviving Stage IIIa (n ϭ 484) 60 Stage IIIc (n ϭ 293) 40 Stage IIIb (n ϭ 73) 20 Stage IVb (n ϭ 150) Stage IVc (n ϭ 47) 0 0 1 2 3 4 5 Years after diagnosis FIGURE 5-10  Carcinoma of the corpus uteri; patients treated in 1990–1992 (FIGO). Survival by surgical stage (n = 5694). [From Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003. © International Federation of Gynecology and Obstetrics.]
  • 16. 156 5.  Adenocarcinoma of the Uterine Corpus TABLE 5-7 Distribution of Endometrial Carcinoma by Stage TABLE 5-8  Relationship between Depth of Myometrial (Surgical) Invasion and Recurrence in Patients with Stage I Endometrial Carcinoma Stage Patients (%) Endometrial only 7/92 (8%) I 3839 (73) Superficial myometrium 10/80 (13%) II 574 (11) Medium myometrium 2/17 (12%) III 694 (13) Deep myometrium 15/33 (46%) IV 166 (3) Modified from DiSaia PJ et al: Am J Obstet Gynecol 151:1009, 1985. From Pecorelli S (ed): J Epidemiol Biostat 3:41, 1998. Myometrial invasion TABLE 5-9  Relationship between Depth of Myometrial Invasion and Five-Year Survival Rate (Stage I) Endometrium Inner Outer Cervical or only half half extrauterine Stage Patients 5-Year Survival (%) involvement IaG1 698 93 Grade 1 IbG1 1030 88 IcG1 442 87 Grade 2 IaG2 229 91 IbG2 1307 93 Grade 3 IcG2 485 84 IaG3 66 75 Low risk Intermediate risk High risk IbG3 280 82 IcG3 247 66 FIGURE 5-11  Risk assignment based on surgical staging/extent of disease in patients with endometrial cancer. From Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003. Report of FIGO demonstrated a decrease in the survival than do those with only fundal disease (8%). There is a rate as myometrial penetration increased (Table 5-9). similar frequency of para-aortic nodal metastases: a 16% Lutz and co-workers determined that the depth of myo- incidence from disease of the lower uterine segment and metrial penetration was not as important as the proxim- a 4% incidence when only fundal disease is present. ity of the invading tumor to the uterine serosa. Patients Previously, endocervical curettage (ECC) was commonly whose tumors invaded to within 5 mm of the serosa had used to determine whether the patient had cervical a 65% 5-year survival rate, whereas patients whose involvement. Many false-positive results occur through tumors were more than 10 mm from the serosa had a the use of this technique, however. In addition, the prog- 97% survival rate. The depth of myometrial invasion is nostic significance of endocervical glandular spread (for- associated with the other prognostic factors, such as the merly stage IIa) has been challenged. The new surgical grade of the tumor. As noted by DiSaia and associates, staging adopted by FIGO in 2009 includes only those the survival rate of patients with poorly differentiated patients with cervical stromal invasion in the stage II lesions and deep myometrial invasion is poor in contrast category. In some cases, cervical biopsy and/or ECC is to that of patients who have well-differentiated lesions required in the pretreatment planning of a patient with but no myometrial invasion. This suggests that virulence suspected cervical involvement. of the tumor may vary considerably, and as a result, Patients with stage III-IV disease may have a hetero- therapy should depend on the combination of prognos- geneous mix of disease characteristics. It is well recog- tic factors. nized that endometrial cancer can and frequently does Location of the tumor within the endometrial cavity metastasize to the adnexa. Patients with adnexal and/ is important because tumors low in the cavity may or serosal involvement are categorized as stage IIIA and involve the cervix earlier than fundal lesions. Prognosis are considered to have a higher risk of peritoneal recur- for women with cervical involvement (stage II) is worse rence. In GOG 33, 5% of patients had adnexal involve- than with stage I disease. Cervical involvement is often ment. Adnexal metastasis was significantly associated a surrogate marker for extrauterine disease spread or for with involved pelvic (32%) and para-aortic (20%) lymph risk of local recurrence. Data from GOG 33 showed that nodes. In a large surgical trial comparing laparoscopy those with disease of the lower uterine segment had a to open staging (GOG Lap 2 trial), 5% of 2616 patients higher incidence of pelvic lymph node metastases (16%) enrolled were found to have stage IIIA disease (FIGO
  • 17. 5.  Adenocarcinoma of the Uterine Corpus 157 TABLE 5-10  Grade vs Positive Pelvic and Aortic Nodes TABLE 5-12 Frequency of Pelvic and Para-Aortic Nodal Disease Grade (n) Pelvic Nodes (%) Aortic Nodes (%) Grade G1 (180) 5 (3) 3 (2) Grade I Grade II Grade III G2 (288) 25 (9) 14 (5) Depth of Invasion (n = 180) (n = 288) (n = 153) G3 (153) 28 (18) 17 (11) Endometrial only 0%/0% 3%/3% 0%/0% Modified from Creasman WT et al: Cancer 60:2035, 1987. (n = 86) Inner one-third 3%/1% 5%/4% 9%/4% (n = 281) Middle one-third 0%/5% 9%/0% 4%/0% (n = 115) TABLE 5-11 Maximal Invasion and Node Metastasis Outer one-third 11%/6% 19%/14% 34%/23% (n = 139) Maximal invasion (n) Pelvic Nodes (%) Aortic Nodes (%) (Pelvic Nodal Positivity/Para-aortic Nodal Positivity) Endometrium only (87) 1 (1) 1 (1) Modified from Creasman WT et al: Cancer 60:2035, 1987. Superficial muscle (279) 15 (5) 8 (3) Intermediate muscle (116) 7 (6) 1 (1) Deep muscle (139) 35 (25) 24 (17) Modified from Creasman WT et al: Cancer 60:2035, 1987. tumors had pelvic nodal metastases of 3%, 9%, and 18% respectively. Similarly, patients with no myometrial invasion, inner one third, middle one third, and outer 1988 staging). In an analysis of 222 patients with clinical one third invasion had 1%, 5%, 6%, and 25% pelvic nodal stage I carcinoma of the endometrium reported by disease, respectively. The highest risk group included DiSaia and colleagues, 16 (7%) were found to have patients with grade III tumors and outer one third inva- metastasis in the adnexa. This finding correlated with sion who had pelvic nodal involvement in 34% of cases many but not all of the other prognostic factors. Spread (Table 5-12). Without a lymphadenectomy, one may to the adnexa did not seem to be related to the size of grossly estimate the probability of nodal involvement the uterus. The grade of the disease did not appear based on these data to select for or against the use of prognostically important in regard to this in that 6% of adjuvant therapy. This strategy potentially results in patients with grade I tumors had adnexal disease com- undertreatment or overtreatment of patients, however. pared with only 10% if poorly differentiated carcinoma In two large prospective randomized trials, routine was present. The depth of invasion did appear to be lymphadenectomy resulted in the identification of more significant, however, in that only 4% of patients with patients with nodal disease (9% to 13%), compared to only the endometrium involved had adnexal spread, when only clinically suspicious nodes were removed compared with 24% who had adnexal metastases if (1% to 3%). It is clear that patients with nodal disease deep muscle was involved. If tumor was limited to the have poorer prognosis (3- to 5-year survival of 50% to fundus of the uterus, only 5% of patients had disease 75%) and different patterns of failure (nodal, distant) in the adnexa; however, if the lower uterine segment or than patients with negative nodes (3- to 5-year survival the endocervix was involved, one-third had spread to of 80% to 95%, vaginal cuff failures predominate). the adnexa. When metastasis was present in the adnexa, Patients with nodal involvement include those with 60% of patients had malignant cells in the peritoneal pelvic nodal disease (IIIC1) or any para-aortic involve- cytologic fluid, compared with only 11% if the adnexa ment (IIIC2). The substaging was created in 2009 given were not involved. Recurrences appeared in only 14% the belief of different outcomes associated with different of these individuals who did not have metastasis to the levels of nodal involvement. The number of involved adnexa, compared with recurrences in 38% of patients nodes and the extent of resection of grossly involved with adnexal metastasis. nodes also affect outcome. In addition Mariani and Metastatic spread to lymph nodes (stage IIIC) has McMeekin have suggested that patients with (+) nodal prognostic and therapeutic implications. It is clear that disease plus other stage III defining features (positive lymphadenectomy is the most sensitive way to identify cytology, adnexal or serosal involvement) have a much nodal disease. The GOG 33 study demonstrated that as poorer prognosis than those with nodal disease only. the depth of tumor invasion or tumor grade increased, Patients with stage IV/distant disease spread (intraperi- the frequency of pelvic and para-aortic nodal metastases toneal, lung, liver) have a particularly poor prognosis, also increased (Tables 5-10 and 5-11). For all 621 patients, with 5-year survival of less than 20%. The extent of sur- 58 (9%) had positive pelvic nodes and 34 (6%) had posi- gical resection has been suggested to alter prognosis in tive para-aortic nodes. Patients with grade 1, 2, and 3 patients with advanced-stage disease. As with ovarian
  • 18. 158 5.  Adenocarcinoma of the Uterine Corpus cancer, the extent of resection of disease reflects biology invasion, whereas patients with a poorly differentiated of the tumor, aggressiveness of the surgery, and response malignant neoplasm might have only endometrial or to postoperative therapies. superficial myometrial involvement. Lymphovascular Space Involvement Tumor Grade Hanson and colleagues described 111 patients with stage The degree of histologic differentiation (tumor grade) of I endometrial cancer and found capillary-like space endometrial cancer is a sensitive indicator of prognosis (CLS) involvement in 16. This was most frequently and is included in FIGO stage assignment. The Annual found in patients with poorly differentiated tumors with Report on the Results of Treatment in Gynecological deep invasion. These patients had a 44% recurrence rate, Cancer has evaluated survival in regard to grade in compared with 2% if the CLS was not involved. This was patients with clinical stage I adenocarcinoma of the an independently significant prognostic factor. In the endometrium (Table 5-13). Tumor grade is inversely GOG study of 621 patients, it was shown that 93 (15%) related to survival decreases; as grade increases, survival had CLS involvement. The incidences of pelvic and is poorer. In their review of 244 patients with stage I para-aortic node metastases were 27% and 19%, respec- disease, Genest and colleagues noted that patients with tively. This compares with a 7% occurrence of pelvic grade I disease had a 5-year survival rate of 96%. This node metastasis and a 3% occurrence of para-aortic node dropped to 79% and 70% for grade II and grade III, metastasis when there is no CLS involvement. In risk respectively. Data presented by Morrow for outcomes in models predicting risk of recurrence in node-negative/ patients enrolled on GOG 33 show that recurrence-free early-stage endometrial cancer, the GOG has suggested survival markedly diminishes with increasing grade, that LVSI is an important risk factor. In the Post Opera- with progression-free survival (PFS) at 48 months being tive Radiation Therapy in Endometrial Cancer (PORTEC) approximately 95%, 85%, and 68% for grade I, II, and III trial, LVSI was considered to be a factor associated with tumors, respectively. Grade of tumor also correlates with distant site of failure. other factors of prognosis. Table 5-14 shows the relation- ship between differentiation of the tumor and depth of Tumor Size myometrial invasion as reported by Creasman from the Schink and co-workers evaluated tumor size in 91 GOG 33 study. As the tumor becomes less differentiated, patients with stage I disease. The incidence of lymph the chances of deep myometrial involvement increase. node metastases in patients with tumor size less than However, exceptions can occur: Patients with a well- 2 cm was only 6%. If tumor was greater than 2 cm in differentiated lesion can have deep myometrial diameter, there were nodal metastases of 21% and up to 40% if the entire endometrium was involved. Patients with lesions greater than 2 cm in size and less than half myometrial invasion had no nodal metastasis. Using TABLE 5-13  Relationship between Tumor Differentiation multivariate analysis, the authors showed that tumor and Five-Year Survival Rate, Stage I (Surgical) size was an independently significant prognostic factor. Grade Survival (n = 5017) (%) Watanabe and associates did not find cancer size was predictive of lymph node metastasis. Gynecologic oncol- 1 91 2 90 ogists from the Mayo Clinic have developed a risk model 3 81 predicting nodal metastases and have suggested that grade I-II tumors that are less than 2 cm are particularly From Pecorelli S (ed): FIGO Annual Report, years 1996–98, Int J Gynecol Obstet 83:95, 2003. low risk for nodal disease. Peritoneal Cytology The importance of peritoneal cytology in endometrial TABLE 5-14  Correlation of Differentiation and Myometrial cancer is controversial. In GOG 33, 76 (12%) had malig- Invasion in Stage I Cancer nant cells identified by cytologic examination of perito- Grade neal washings. Of these patients, 25% had positive pelvic nodes, compared with 7% of patients in whom no malig- Myometrial Invasion 1 (%) 2 (%) 3 (%) nant cells were found in peritoneal cytologic specimens None 24 11 11 (P > 0.0001). It is true that peritoneal cytology, to a certain Superficial 53 45 35 degree, mimics other known prognostic factors—that is, Mid 12 24 16 if peritoneal cytologic specimens are positive, other Deep 10 20 42 known poor prognostic factors may also be identified. Modified from Creasman WT et al: Cancer 60:2035, 1987. In addition, data from GOG 33 also suggested that the