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Screening and Etiology
Cancer of the uterine corpus is the most common gynecologic malignancy. Approximately 36,000 women per year develop uterine cancer in the United States, making it the fourth most common cancer in women. Unopposed estrogen use results in a fourfold increase in adenocarcinoma of the endometrium. Fortunately, the use of progestins has decreased this risk.
The incidence of endometrial cancer in the United States is approximately 0.7 per 1,000 women. Screening and autopsy studies suggest that there may be many occult, undiagnosed endometrial cancers.
Endometrial adenocarcinoma occurs during both the reproductive and the menopausal years. The median age of onset is 61 years; the largest number of affected patients are between the ages of 50 and 59 years. Almost one fourth of all adenocarcinomas of the endometrium are diagnosed before menopause cancer of the uterus.
Multiple factors have been associated with adenocarcinoma of the endometrium. The use of combination oral contraceptives decreases the risk of endometrial cancer. Women who use oral contraceptives have a 0.5 risk ratio (relative risk) of developing endometrial cancer compared with those who have never used oral contraceptives. This protection occurs with as little as 12 months of use, and protection continues for at
Two distinct phenotypes are associated with the onset of endometrial cancer. The first is women with late-onset menopause who are obese and nulliparous. If all three factors are present, the risk for developing endometrial cancer is increased by about fivefold. Such patients tend to have well-differentiated, superficially invasive cancer for which simple
A second phenotype is characterized as nonestrogenic. These women tend to be multiparous, thin, and African American, and they usually have histologically poorly differentiated, deeply invasive lesions that may
There is growing concern that the increased use of tamoxifen for therapeutic and prophylactic indications in breast cancer may lead to an increased number of endometrial cancers. Tamoxifen is an antiestrogen that
All of the prospective, randomized studies that identified endometrial cancers in breast cancer patients receiving tamoxifen therapy were designed to evaluate the efficacy of the drug in breast cancer, but did not examine the safety issues of the drug. Patients taking tamoxifen therapy develop uterine bleeding and have other gynecologic symptoms to a greater degree than those not taking tamoxifen. Prospective, randomized studies comparing the number of endometrial cancers in the tamoxifen group with the number in the no-tamoxifen group suggest, but do not positively identify, a relationship between tamoxifen and this cancer. To date, 15 studies have compared tamoxifen either with placebo or no drug in varying doses for different time intervals with nonuniform median follow-up times. Of these studies, 12 noted no difference in the number of endometrial cancers between the tamoxifen and the no-tamoxifen groups, one noted a significantly decreased incidence of endometrial cancer in the tamoxifen group, and two noted an increased number of corpus cancers in the tamoxifen group.
The latter two studies have received tremendous notoriety. They are the National Surgical Adjuvant Breast Project study and the Stockholm study. A total of 42 corpus cancers were reported in these two studies. Approximately 5,000 patients taking tamoxifen for various periods and at different doses were compared with patients not taking tamoxifen. The number dropped to 14 using a very conservative latency period of 2 years, as well as elimination of non-adenocarcinoma malignancies, those who were randomized to take tamoxifen.
Diagnosis
The cost of screening for adenocarcinoma and its precursors in the total population would be prohibitive. The most common symptom of corpus cancer is uterine bleeding. Of all endometrial cancers, 75% occur in the postmenopausal patient, although only 20% of postmenopausal women will have a genital malignancy.
Prognostic Characteristics
Multiple prognostic factors have been identified in endometrial adenocarcinoma. Patient age, histology, degree of differentiation, depth of invasion, and surgical staging are all important prognostic factors. Younger patients have a better prognosis than older individuals. This may be because younger patients tend to have a better-differentiated, superficially invasive cancer. Adenocarcinoma with its variants are by far the most common histologic type. Current data suggest that grade of adenocarcinoma is a more important prognostic factor.
Staging
Many of the prognostic factors noted above require surgical staging for adequate delineation. Until 1988, staging for endometrial cancer was clinical. It became readily apparent that clinical staging failed to identify the true extent of disease in a large number of patients. Up to one fourth of patients who were thought to have clinical stage disease I had extrauterine disease when surgical staging was done. The margin of error for stage II was even greater, with studies suggesting that 50-60% of patients.
Endometrial cancer is a surgically staged disease, and many of the traditional diagnostic procedures advocated before 1988 are no longer necessary. These include a fractional dilation and curettage and endocervical curettage. A chest X-ray is important pretreatment and could affect final staging.
Staging for Carcinoma of the Corpus Uteri
Stage IA G 1, 2, 3 Tumor limited to endometrium
Stage IB G 1, 2, 3 Invasion to less than one half of the myometrium
Stage IC G 1, 2, 3 Invasion to more than one half of the myometrium
Stage IIA G 1, 2, 3 Endocervical glandular involvement only
Stage IIB G 1, 2, 3 Cervical stromal invasion
Stage IIIA G 1, 2, 3 Tumor invades serosa and/or adnexa, and/or positive peritoneal cytology
Stage IIIB G 1, 2, 3 Vaginal metastases
Stage IIIC G 1, 2, 3 Metastases to pelvic and/or paraaortic lymph nodes
Stage IVAG 1, 2, 3 Tumor invasion of bladder and/or bowel mucosa
Stage IVB Distant metastases including intraabdominal and/or inguinal lymph nodes
Histopathology--Degree of Differentiation
Cases of carcinoma of the corpus should be classified (or graded) according to the degree of
histologic differentiation as follows:
G1 = 5% or less of a nonsquamous or nonmorular solid growth pattern
G2 = 6-50% of a nonsquamous or nonmorular solid growth pattern
G3 = more than 50% of a nonsquamous or nonmorular solid growth pattern
Notes on Pathological Grading
1. Notable nuclear atypia, inappropriate for the architectural grade, raises the grade of a grade 1 or grade 2 tumor by 1.
2. In serous adenocarcinomas, clear-cell adenocarcinomas, and squamous cell carcinomas, nuclear grading takes precedence.
3. Adenocarcinomas with benign squamous differentiation are graded according to the
Therapy
Simple hysterectomy and bilateral salpingo-oophorectomy remain the hallmarks of therapy for corpus cancer. After complete surgical staging, if disease is limited to the uterus, most patients need no further therapy. The one exception is patients with a poorly differentiated, deeply invasive cancer.
The role of brachytherapy postoperatively does not appear to be efficacious in most surgical stage I cancers because vaginal vault recurrence appears to be no more than 1-2%.
Recurrent disease historically has been treated in many different ways. If a local recurrence appears in the vaginal vault, surgery alone or in combination with radiation therapy has saved many of these patients. If recurrence is in the lower vagina, success has been limited. For metastatic disease, progestins have been primarily used; reports have noted an objective response in about one third of patients. More recent data suggest that the response rate is 15-20%. Original grade of tumor, length of time from primary treatment to recurrence, and hormone receptor status of the original tumor all appear to be indicative of the patient's response to progestin. Several cytotoxic agents have been used with objective responses noted. The most experience has been with adriamycin and cyclophosphamide, cisplatin with or without adriamycin, and more recently paclitaxel. Unfortunately, when there is a response, it is relatively short lived. The ideal single or combination regimen for recurrent endometrial cancer has not yet been identified.
Estrogen Replacement Therapy after Endometrial Cancer
Estrogen replacement therapy can be used safely in patients who have had endometrial cancer. This suggestion is based on the fact that patients with a disease with a good prognosis, although
Endometrial Hyperplasia
Both the diagnosis and management of endometrial hyperplasia have generated tremendous confusion. The natural history would suggest that some of these lesions revert to normal spontaneously or with medical therapy, some persist, and a few will progress to endometrial adenocarcinoma and uterus cancer.