ENDOMETRIAL CANCER
Carcinoma of the epithelial lining (endometrium) of the uterine corpus is the most common female pelvic malignancy. Factors influencing its prominence are the declining incidence of cervical cancer, longer life expectancy, and earlier diagnosis. Adenocarcinoma of the endometrium, the most prevalent histologic subtype, is currently the fourth most common cancer in women, with 39,080 new cases, ranking behind breast, lung, and bowel cancers. Endometrial adenocarcinoma is the eighth leading cause of death from malignancy in women, accounting for 7,400 deaths this year.
Epidemiology
Age Endometrial cancer is primarily a disease of postmenopausal women, although 25% of cases occur in premenopausal patients, with 5% of cases developing in patients < 40 years old.
Geography The incidence of endometrial cancer is higher in Western nations and very low in Eastern countries.
Immigrant populations tend to assume the risks of native populations, highlighting the importance of environmental factors in the genesis of this disease. Endometrial cancers tend to be more common in urban than in rural residents. In the United States, white women have a twofold higher incidence of endometrial cancer than black women.
Etiology and risk factors
Adenocarcinoma of the endometrium may arise in normal, atrophic, or hyperplastic endometrium. Two mechanisms are generally believed to be involved in the development of endometrial cancer. In approximately 75% of women, there is a history of exposure to unopposed estrogen, either endogenous or exogenous (type I). The tumors in these women begin as endometrial hyperplasia and progress to carcinomas, which usually are better differentiated and have a favorable prognosis.
In the other 25% of women, carcinomas appear spontaneously, are not clearly related to a transition from atypical hyperplasia, and rather arise in a background of atrophic or inert endometrium. These neoplasms tend to be associated with a more undifferentiated cell type and a poorer prognosis (type II).
Unopposed estrogen It has been hypothesized that longterm estrogenic stimulation of the endometrium unmodified by progesterone has a role in the development of endometrial carcinoma. This hypothesis derives from observations that women who are infertile or obese or who have dysfunctional bleeding due to anovulation are at high risk for this disease, as are women with estrogen-secreting granulosa theca cell ovarian tumors. Also, the recognition that atypical adenomatous (complex) hyperplasia is a precursor of cancer, and that it is associated with unopposed estrogen in women, underscores the importance of the association among risk factors, estrogens, and cancer. In the late 1970s and early 1980s, several casecontrol studies demonstrated that the risk of endometrial cancer is increased 4–15fold in longterm estrogen users, as compared with agematched controls.
It is well established that past use of oral contraceptive pills protects against endometrial cancer. Maxwell et al presented a retrospective review of the US Cancer and Steroid Hormone (CASH) study to determine the effects of progestin potency. They evaluated 417 endometrial cases and 2,452 controls. It appeared that there may be an increased benefit in the higher potency progestins (overall response = 0.3 [95% confidence interval (CI): 0.2–0.6]) vs lower potency progestins (overall response = 0.5 [95% CI: 0.3–0.6]), although these differences were not significant. They also suggested that in women with a higher body mass index (BMI), the higher potency progestins might be more protective. Higher progestin dose has a greater effect on decreasing risk.
Diet The high rate of occurrence of endometrial cancer in Western societies and the very low rate in Eastern countries suggest a possible etiologic role for nutrition, especially the high content of animal fat in Western diets. There may be a relationship between highfat diets and the higher incidence of endometrial carcinoma in women with conditions of unopposed estrogen: Endogenous estrogens rise in postmenopausal women because of increased production of androstenedione or a greater peripheral conversion of this hormone to estrone. In obese women, the extraglandular aromatization of androstenedione to estrone is increased in fatty tissue.
Obesity Phenotypically, the majority of women who develop endometrial cancer tend to be obese. Women who are 30 pounds over ideal weight have a 3fold increased risk of developing endometrial cancer, whereas those 50 pounds or more over ideal weight have a 10-fold increased risk.
Parity Nulliparous women are at 2 times greater risk of developing endometrial cancer, females who undergo menopause after age 52 are at 2.5 times greater risk, and those who experience increased bleeding at the time of menopause are at 4 times greater risk.
Other risk factors Other known risk factors for endometrial cancer include diabetes mellitus; hypertension; endometrial hyperplasia; and a family history of endometrial, breast, and/or colon cancer. Diabetic females have a 3-fold increased risk, and hypertensive patients have a 1.5-fold greater risk of endometrial cancer. Whereas patients found to have simple endometrial hyperplasia have a low risk of disease progression to cancer, 29% of those with complex atypical hyperplasia, if left untreated, will develop adenocarcinoma.
Tamoxifen exerts its primary effect by blocking the binding of estrogen to estrogen receptors. It also exerts mild estrogenic effects on the female genital tract. This weak estrogenic effect presumably accounts for an increased frequency of endometrial carcinoma observed in women receiving prolonged adjuvant tamoxifen therapy for breast carcinoma.
Initially reported in 1985, the increased frequency of endometrial carcinoma in patients treated with tamoxifen was characterized more fully in a study of 1,846 women recorded in the Swedish Cancer Registry. This study reported a 6.4-fold increase in the relative risk of endometrial carcinoma with a daily dose of 40 mg of tamoxifen. The greatest cumulative risk was observed after 5 years of tamoxifen use.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) subsequently reported on the incidence of other cancers in 2,843 women with node-negative, estrogen-receptor–positive breast cancer treated with either tamoxifen or placebo in its B-14 randomized trial and an additional 1,220 patients treated with tamoxifen in another NSABP trial. The relative risk of endometrial carcinoma in the tamoxifen-treated patients was 7.5. The hazard rate was 0.2 per 1,000 cases with placebo and 1.6 per 1,000 cases with tamoxifen therapy. The mean duration of tamoxifen therapy for all patients was 35 months, and 36% of the cancers had developed by 2 years after the initiation of treatment. A more recent review of NSABP treatment and prevention trials revealed that the risk of uterine sarcomas was also increased with tamoxifen. The incidence of sarcomas was very low, however, with a rate of 0.17/1,000 women/year.
These data raise the question of whether tamoxifen should be used as adjuvant therapy for women at relatively low risk for breast cancer recurrence. First, it should be recognized that the endometrial cancers that develop in patients receiving tamoxifen exhibit the same stage, grade, and prognosis distribution as other endometrial cancers. There is some evidence that tamoxifen use is associated with an increased risk of uterine sarcoma; fortunately, this risk is low, and the cure rate should be high. Second, adjuvant tamoxifen reduces the cumulative rate of recurrence of breast cancer from 228 to 124 cases/1,000 women and the cumulative rate of second primary breast cancers from 40.5 to 23.5 cases/1,000 women.
When all of these facts are taken into account, there is an overall 38% reduction in the cumulative hazard rate for recurrence of breast cancer in tamoxifen-treated patients. Thus, the benefits of tamoxifen outweigh the risks of endometrial cancer.
The current recommendations for screening women on tamoxifen are to educate patients about the significance of abnormal spotting, bleeding, or discharge and to investigate promptly any of these abnormalities.
Some experts have proposed that tamoxifen-treated women be screened with transvaginal ultrasonography. However, recent data suggest a high false-positive rate and a low frequency of significant findings, leading to the conclusion that endometrial screening is not warranted.
