Endometrial cancer is the fourth most common cancer in women, accounting for approximately 6,000 deaths per year in the United States. It is more common in women who are older, white, affluent, obese and of low parity. Hypertension and diabetes mellitus are also predisposing factors. Because any condition that increases exposure to unopposed estrogen increases the risk of endometrial cancer, tamoxifen therapy, estrogen replacement therapy without progestin and the presence of estrogen-secreting tumors are all risk factors. Smoking and the use of oral contraceptives appear to decrease the risk. Women with an increased risk and those with postmenopausal bleeding should be screened for endometrial cancer. Endometrial sampling is currently the most accurate and widely used screening technique, but ultrasonographic measurement of endometrial thickness and hysteroscopy have also been studied. Patients with endometrial specimens that show atypia have about a 25 percent likelihood of progressing to carcinoma, compared with less than 2 percent in patients without atypia. Endometrial cancer is usually treated surgically, but in patients with appropriate pathologic findings who decline surgical treatment, progestin therapy may be satisfactory.
Uterine cancer, the most common malignant neoplasm of the female genital tract and the fourth most common cancer in women, is currently diagnosed in about 34,000 women each year. In 1997, about 6,000 women in the United States died of this disease.1 It is more frequent in affluent and white women, especially obese, postmenopausal women of low parity.2 Hypertension and diabetes mellitus are also predisposing factors.3 Uterine cancer is most frequently diagnosed in industrialized western nations, with the lowest rates occurring in India and Southeast Asia.2
Advances in the past two decades have expanded our knowledge of endometrial cancer, giving us a better definition of the histologic subtypes and providing us with better screening and surgical tools with which to diagnose and treat this disease.2
Pathogenesis
It was originally hypothesized that endometrial hyperplasia represented a morphologic continuum from benign cystic hyperplasia to atypical complex hyperplasia, which may be the immediate precursor of endometrial carcinoma.2 Several recent studies have suggested that endometrial hyperplasia and endometrial cancer are two different entities, and the distinguishing feature is the presence or absence of cytologic atypia.2 Studies have shown that patients who have endometrial hyperplasia without atypia respond well to progestin therapy and are not at increased risk for cancer; however, patients with cytologic atypia show only a 50 percent response to progestin therapy, and cancer develops in 25 percent of cases.4-6
Uterine cancer is a general term used to describe many different histopathologic types of tumors found in the uterus. The most common cancer of the uterus is adenocarcinoma. Several other histologic subtypes also occur (Table 1). The less common forms are associated with a lower overall survival rate and a higher risk of metastatic disease at the time of surgical staging.2 Patients with serous (also known as papillary serous) and clear cell carcinomas tend to be older than those with other types (mean age: 66 versus 59 years) and are more likely to have abnormal cervical cytology.7 Serous carcinoma invades the myometrium and lymph-vascular spaces early and has been shown to metastasize without deep myometrial invasion.2
Risk Factors
Any characteristic that increases exposure to unopposed estrogen increases the risk for endometrial cancer (Table 2).2,4-8 Conversely, decreasing exposure to estrogen limits the risk. Unopposed estrogen therapy, obesity, anovulatory cycles and estrogen-secreting neoplasms all increase the amount of unopposed estrogen and thereby increase the risk for endometrial cancer. Smoking seems to decrease estrogen exposure, thereby decreasing the cancer risk, and oral contraceptive use increases progestin levels, thus providing protection.9 Tamoxifen (Nolvadex) therapy, often used in women with breast cancer, has an estrogenic effect on the female genital tract and, through this unopposed estrogen exposure, increases the risk for endometrial cancer.10 Physicians should be aware that endometrial ablation is not a treatment for endometrial hyperplasia or carcinoma, and a previous ablation does not protect against the development of endometrial disease.
Hormone Replacement Therapy
Unopposed estrogen treatment of menopause is associated with an eightfold increased incidence of endometrial cancer.11,12 The addition of progestin decreases this risk dramatically.12 For maximum endometrial protection, administration of medroxyprogesterone acetate (Provera), in a dosage of 10 mg daily, or norethindrone acetate (Aygestin), in a dosage of 2.5 mg daily, for a minimum of 12 to 14 days per month has been recommended.13 However, some physicians prescribe lower dosages, either 5.0 or 2.5 mg of medroxyprogesterone daily.
A 13-day “progestin challenge” course of either 10 mg of medroxyprogesterone or 2.5 to 5 mg of norethindrone given to postmenopausal women resulted in withdrawal bleeding and correlated with a high likelihood of endometrial pathology.13 In this study, it was found that low dosages may not provide maximal endometrial protection.13 However, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial14 found no difference in the risk for endometrial disease between patients taking placebo and those taking estrogen with medroxyprogesterone, in a dosage of either 10 mg per day for 12 days or 2.5 mg per day continuously.
One possible explanation for these contradictions can be found in the patient groups studied. Many of the patients in one study had one or more risk factors for endometrial disease,13 whereas the PEPI trial involved a randomly selected cohort.14 These findings suggest that patients at high risk for endometrial disease should receive higher dosages of progestins than patients at low risk, a suggestion that is supported, in theory, by the pathophysiology. Further studies may be necessary for more definitive recommendations

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