Carcinoma of the epithelial lining (endometrium) of the uterine corpus is the most common female pelvic malignancy, with 54,870 new cases estimated to be diagnosed in 2015 and 10,170 deaths expected. Factors influencing its prominence are the declining incidence of cervical cancer, longer life expectancy, and earlier diagnosis.
Endometrial cancer is primarily a disease of postmenopausal women, although 25% of cases occur in premenopausal patients, with 5% of cases developing in patients younger than 40 years.
The incidence of endometrial cancer is high 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, the incidence of endometrial cancer is twice as high in white women as in black women.
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 more favorable prognosis than tumors unrelated to estrogens.
In 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).
It has been hypothesized that long-term 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 use in women, underscores the importance of the association among risk factors, estrogens, and cancer. In the late 1970s and early 1980s, several case-control studies demonstrated that the risk of endometrial cancer is increased 4- to 15-fold in long-term estrogen users, as compared with age-matched controls.
It is well established that past use of oral contraceptives (OCs) protects against endometrial cancer. The use of OCs with either high-potency progestin or low-potency progestin is associated with a decreased risk of endometrial cancer. The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. OCs with higher progestin potency may be more protective than OCs with lower progestin potency among women with a larger body habitus.
Sidebar: The Women’s Health Initiative enrolled 16,608 postmenopausal women from 40 US clinical centers into a randomized, double-blind, placebo-controlled trial. Women aged 50 to 70 with an intact uterus and normal endometrial histology were assigned to once-daily 0.625-mg conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate or to placebo. After 6 years of the intervention and 7 years of additional follow-up, endometrial cancer was diagnosed in 66 women in the combined-hormone–therapy group and in 95 women in the placebo group, which translated to a 35% reduction in risk (P = .007) (Chlebowski RT, Anderson GL, Sarto G, et al: European Cancer Congress abstract LBA13, 2013).
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 high-fat 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.
Phenotypically, the majority of women who develop endometrial cancer tend to be obese. Women who are 30 lb over ideal weight have a threefold increased risk of developing endometrial cancer, whereas those 50 lb or more over ideal weight have a 10-fold increased risk.
Nulliparous women are at 2 times greater risk for developing endometrial cancer, women 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.
It is believed that the majority of endometrioid neoplastic lesions of the endometrium follow a continuum of histologically distinguishable hyperplastic lesions that covers a spectrum ranging from endometrial hyperplasia without atypia to endometrial hyperplasia with atypia (AEH) to well-differentiated 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. However, the reproducibility of these diagnoses has been questioned by many.
As recently reported, the Gynecologic Oncology Group (GOG)-0167 estimated the reproducibility of a referring institution’s pathologist’s diagnosis of AEH and determined the frequency of concomitant adenocarcinoma in the hysterectomy obtained within 12 weeks of the initial diagnosis. The referring institution’s pathologist’s diagnosis of AEH was supported by the majority of the expert panel in only 38% of cases. The majority diagnosis was adenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases. Unanimous agreement on any diagnosis was reached among the entire expert panel in only 40% of cases. This study panel found that there was a high incidence (43%) of endometrial cancer in patients who had a biopsy demonstrating AEH.
Other risk factors
Other known risk factors for endometrial cancer include diabetes mellitus; hypertension; and a family history of endometrial, breast, and colon cancer. Diabetic women have a 3-fold increased risk, and hypertensive patients have a 1.5-fold greater risk of endometrial cancer. Results from three hereditary nonpolyposis colorectal cancer (HNPCC) registries have shown a 10-fold increased risk of endometrial cancer for women who carry the HNPCC genetic abnormality, with a cumulative risk for endometrial cancer of 43% by age 70. Women with or at risk for HNPCC can be offered endometrial screening annually beginning at age 35, but informed decision making after a discussion of options, including benefits, risks, and limitations of testing, is appropriate. Additional investigation is needed to determine the appropriate monitoring for endometrial cancer in HNPCC carriers.
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 per 1,000 women and the cumulative rate of second primary breast cancers from 40.5 to 23.5 cases per 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 may outweigh the risks of endometrial cancer.
The current recommendations for screening women who are receiving 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.