Endometrial Cancer: Recent Developments in Evaluation and Treatment

Introduction

In the United States, an estimated 37,400 women will develop uterine cancer in 1999 and an estimated 6,400 women will die of the disease.[1] The incidence of this cancer varies throughout the world, with more women in industrialized countries being afflicted. Carcinoma of the endometrium is the most common gynecologic malignancy among US women, who have a lifetime risk of developing the disease of approximately 2%.

Fortunately, the majority of cases of endometrial cancer are diagnosed at an early stage, when surgery alone may be adequate for cure. The rate of 5-year survival for women with stage I endometrial cancer is as high as 95%; however, the 5-year survival rate for women with stage III or IV disease is only 26%.[2]

Great strides have been made in our understanding of endometrial cancer over the past decade. The etiologic role of estrogen therapies, including the use of hormone replacement and tamoxifen(Drug information on tamoxifen) (Nolvadex), has been the focus of several studies. The protective benefits of oral contraceptive pills and progestin therapies have been well established. Surgical staging can be tailored to the individual patient, both by using the laparoscope to minimize surgical morbidity and by modifying the extent of tissue sampling based on histopathologic risk. For advanced or recurrent disease, more active chemotherapeutic agents are available as well, with many ongoing clinical trials.

Risk Factors

Unopposed Estrogens(Drug information on estrogens)

Most of the risk factors for endometrial carcinoma are associated with increased estrogen exposure, either exogenous or endogenous. Examples of increased exogenous exposure include the use of estrogen replacement therapy or tamoxifen, while increased endogenous estrogen exposure may stem from obesity, anovulatory cycles, and estrogen-secreting tumors (Table 1).[3-5]

Obesity and infertility are significant risk factors for the development of this cancer. Excessive adipose tissue is a site of conversion of androstenedione to estrone(Drug information on estrone), as well as aromatization of androgens to estradiol(Drug information on estradiol). Nulliparity, by itself, probably does not increase the risk of endometrial cancer, but rather, the association lies with anovulatory cycles and the lack of a progestin effect during the luteal phase.

With respect to exogenous estrogen exposure, the risk of endometrial cancer is increased in women using combination hormone therapy, even when cyclical progestin therapy is added to an estrogen. In a case-control study, Beresford et al found that women taking unopposed estrogens had a relative risk of endometrial cancer of 4.0 (95% confidence interval [CI], 3.1 to 5.1).[6] In women who took more than 5 years of hormone therapy that included a progestin for less than 10 days per month, the relative risk of endometrial cancer was 4.8 (95% CI, 2.0 to 11.4). Women who used hormone therapy with a progestin for 10 to 21 days per month had a relative risk of 2.7 (95% CI, 1.2 to 6.0).

This study is limited by its retrospective case-control design, which relies on patient recall. However, it suggests the need for additional investigation.

The use of oral contraceptives has consistently been shown to decrease the risk of endometrial and ovarian cancer. The Cancer and Steroid Hormone (CASH) study demonstrated that women using combination oral contraceptives for at least 12 months had a 0.6 (95% CI, 0.3 to 0.9) relative risk of endometrial cancer, as compared with those who had never used oral contraceptives.[7] The protective effects of oral contraceptives were found to persist even 15 years after their use ceased.

Current low-dose oral contraceptives prevent pregnancy primarily through a progestin effect. Similarly, the benefits of oral contraceptives in reducing endometrial cancer risk are also likely related to the effects of progestin in suppressing endometrial proliferation.

Family history also contributes to the risk of endometrial cancer. In women with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, endometrial cancer is the second most common malignancy, with an incidence of 20% to 40%.[8] A site-specific endometrial cancer syndrome also has been suggested from pedigree analysis and population-based studies.[9]

Tamoxifen

As the most commonly diagnosed cancer among US women, breast cancer has a far greater impact than endometrial cancer, the most common gynecologic malignancy. Tamoxifen, a nonsteroidal estrogen with antiestrogenic activity, is commonly used in the adjuvant treatment of women with breast cancer and as therapy for recurrent disease. Tamoxifen also recently received FDA approval for use in reducing the risk of breast cancer in high-risk women. The divergent activity of tamoxifen in different tissues is well recognized; it suppresses the growth of breast tissue (ie, acts as an estrogen antagonist) but stimulates the endometrial lining (ie, has estrogen-agonistic effects).

Both the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Stockholm Breast Cancer Study Group identified an increased risk for endometrial cancer among breast cancer patients treated with tamoxifen.[10,11] In one retrospective, case-control study from the Netherlands, use of tamoxifen for more than 2 years was associated with a 2.3-fold increased risk of endometrial cancer.[12] Conversely, another case-control study from Japan, which controlled for the total dose of tamoxifen exposure, did not find a significant increase in the incidence of subsequent endometrial cancer.[13] The consensus of most studies, however, is that there is a two- to threefold increased risk of endometrial cancer attributable to tamoxifen.[5] Despite initial reports, more recent studies do not confirm that tamoxifen use is associated with high-risk histology endometrial cancers.[11,14,15]

In tamoxifen-treated postmenopausal breast cancer patients, endometrial polyps are a common histopathologic finding. Lahti et al compared 51 postmenopausal women with breast cancer treated with tamoxifen (20 to 40 mg/d) for a median duration of 30 months to 52 breast cancer patients who were not treated with tamoxifen.[16] Endometrial thickening was markedly increased in the tamoxifen-treated women compared with the controls (mean thickness, 10.4 vs 4.2 mm), and polyps also occurred more frequently in the tamoxifen recipients (36% vs 10%).

Similarly, Kedar et al performed a randomized, double-blind, placebo-controlled trial in which 51 of 111 postmenopausal women with breast cancer were treated with tamoxifen (20 mg/d) for a median duration of 22 months.[17] Again, greater endometrial thickening and more endometrial polyps were seen in the women randomized to tamoxifen. In addition, a proliferative process was noted in the endometrium of 90% of the tamoxifen-treated patients, as compared with 39% of the placebo-treated patients.

Endometrial cystic atrophy may also be a common process related to the estrogenic effect of tamoxifen that is not readily detected by curettage but is only diagnosed in patients undergoing hysterectomy.[18] In a cohort of 35 tamoxifen-treated postmenopausal women, endometrial polyps were found in 66% of patients. Endometrial cystic atrophy was noted in 9 of 11 patients who underwent hysterectomy, as compared with only 1 of 24 patients who underwent hysteroscopy and curettage.

Cystic atrophy may not always develop at the surface of the endometrium but may be present deeper within the uterine wall and, thus, still produce endometrial thickening on pelvic ultrasound. Sonohysterography may be helpful in differentiating between polyps and endometrial cystic atrophy in women with a thickened endometrium (see “Presentation and Diagnostic Evaluation” below).

In 1996, the American College of Obstetricians and Gynecologists (ACOG) issued a committee opinion regarding the role of tamoxifen in endometrial cancer.[5] The committee concluded that although tamoxifen is associated with an increased risk of endometrial cancer, the benefits of treatment outweigh the risks.

Although routine screening for endometrial cancer is not recommended for patients taking tamoxifen, many patients are being screened. Certainly, any abnormal bleeding or spotting should be investigated. Because of the high incidence of cystic atrophy, pelvic ultrasound may lead to false-positive results. Rather, endometrial biopsy is a more specific evaluation that may be combined with sonohysterography.