Uterine Corpus Cancer

Epidemiology and Etiology

There are two different clinicopathologic types of endometrial carcinoma ( Table 41-1 ): an estrogen-dependent and a non–estrogen-dependent type.

Any factor that increases exposure to unopposed estrogen increases the risk for type I endometrial cancer. If the proliferative effects of estrogen are not counteracted by a progestin, endometrial hyperplasia and possibly adenocarcinoma can result.

Obesity results in an increased extraovarian aromatization of androstenedione to estrone. Androstenedione is secreted by the adrenal glands, whereas the increased peripheral conversion occurs predominantly in fat depots, as well as in the liver, kidneys, and skeletal muscles. Granulosa-theca cell tumors of the ovary produce estrogen, and up to 15% of patients with these tumors have an associated endometrial cancer.

Unopposed estrogenic stimulation from anovulatory cycles occurs in patients who have polycystic ovarian syndrome (Stein-Leventhal syndrome) and in patients with a late menopause. In postmenopausal women taking estrogen replacement without a pro­gestin for menopausal symptoms, the risk of cancer developing appears to be both dose-dependent and duration-dependent. This increased risk varies from 2- to 14-fold compared with nonusers. The addition of progestin in a cyclic fashion for 10 to 14 days of the month or in a continuous fashion daily throughout the month eliminates this increased risk. Women taking tamoxifen for breast cancer have a two- to threefold increased risk of endometrial cancer. Young women who use oral contraceptives have been shown to have a lower incidence of subsequent endometrial cancer.

About 5% of endometrial cancers occur in women with Lynch syndrome, which is also called the hereditary nonpolyposis colon cancer (HNPCC) syndrome. This syndrome is caused by germline mutations in the DNA mismatch repair genes. Women with the HNPCC syndrome have about a 40% risk of developing endometrial cancer, usually before the menopause. Their risk of developing bowel cancer is also about 40%.

Screening of Asymptomatic Women

Population screening for endometrial cancer is not feasible, because there is no simple method of cancer detection available. However, screening may be justified for high-risk women, including those with a family history of HNPCC syndrome, those with polycystic ovarian disease, and any woman with an intact uterus taking unopposed estrogen. Only about 50% of women with endometrial cancer will have malignant cells on a Papanicolaou smear.

Since the 1990s, transvaginal ultrasonography has increasingly been used for endometrial evaluation. Almost all women with endometrial hyperplasia or carcinoma will have an endometrial thickness of 5 mm or more. Tamoxifen produces a confusing ultrasonic image, which leads to frequent false-positive reports.

Symptoms

The most common symptom of endometrial cancer is abnormal vaginal bleeding, which is present in 90% of patients. Postmenopausal bleeding is always abnormal and must be investigated. The most common conditions associated with postmenopausal bleeding are listed in Table 41-2 . In the premenopausal or perimenopausal patient, diagnosis is often delayed because frequent or heavy bleeding is usually thought to be dysfunctional in nature.

As menopause approaches, menstruation often becomes lighter and less frequent. If the bleeding becomes heavier or more frequent, it should be investigated.

Signs

A general physical examination may reveal obesity, hypertension, and the stigmata of diabetes mellitus. Evidence of metastatic disease is unusual at initial presentation, but the chest should be examined for any effusion and the abdomen carefully palpated and percussed to exclude ascites, hepatomegaly, or evidence of upper abdominal masses.

On pelvic examination, the external genitalia are usually normal. The vagina and cervix are also usually normal, but they should be inspected and palpated carefully for evidence of involvement. A patulous cervical os or a firm, expanded cervix may indicate extension of disease from the corpus to the cervix. The uterus may be of normal size or enlarged, depending on the extent of the disease and the presence or absence of other uterine conditions, such as adenomyosis or fibroids. The adnexa should be palpated carefully for evidence of extrauterine metastases or an ovarian neoplasm. A granulosa cell tumor or an endometrioid ovarian carcinoma may occasionally coexist with endometrial cancer.

Diagnosis

Any woman who presents with postmenopausal bleeding should undergo transvaginal ultrasonography. If the endometrial thickness is greater than 4 mm, endometrial evaluation is necessary. An outpatient endometrial biopsy is usually feasible with a sampling device such as a Pipelle, GynoSampler, or Vabra aspirator. Outpatient endometrial biopsy has a diagnostic accuracy of about 95%. If the endometrial biopsy reveals endometrial cancer, definitive treatment can be arranged. If the endometrial biopsy is negative for cancer or reveals endometrial hyperplasia, a hysteroscopy and fractional dilation and curettage should be performed with the patient under general anesthesia. Specimens from the endometrium and endocervix should be submitted separately for histologic evaluation to determine whether the tumor has extended to the endocervix.

In a premenopausal patient with high-risk factors and abnormal uterine bleeding, the endometrium must be sampled. If there are no high-risk factors present, failure to respond to medical management or a suspicious transvaginal ultrasound is also an indication for hysteroscopy and uterine curettage.

Preoperative Investigations

In addition to a thorough physical examination, blood studies should include a complete blood count; determinations of hepatic enzymes, serum electrolytes, blood urea nitrogen, and serum creatinine; and a coagulation profile. A routine urinalysis should be performed. It is usual to perform computed tomography (CT) of the chest, pelvis, and abdomen, particularly in high-risk cases, to detect any enlarged lymph nodes, liver or lung metastases, hydronephrosis, or adrenal masses. Magnetic resonance imaging is useful for differentiating superficial from deep myometrial invasion or detection of cervical involvement. It may be useful for triaging patients to a gynecologic oncologist.

Pathologic Features

About 75% of endometrial cancers are pure adenocarcinomas. When squamous elements are present, the tumor is called an adenocarcinoma with squamous differentiation. Such tumors are graded on the glandular component of the lesion. Less often, clear cell, squamous, or serous carcinomas occur, and all carry a worse prognosis.

Invasive adenocarcinoma of the endometrium demonstrates proliferative glandular formation with minimal or no intervening stroma. Tumor grade is determined by both the degree of abnormality of the glandular architecture and the degree of nuclear atypia. A lesion that is well differentiated (grade 1) forms a glandular pattern similar to normal endometrial glands ( Figure 41-1 ). A moderately well-differentiated lesion (grade 2) has glandular structures admixed with papillary, and occasionally solid, areas of tumor. In a poorly differentiated lesion (grade 3), the glandular structures have become predominantly solid with a relative paucity of identifiable endometrial glands ( Figure 41-2 ).