Endometrial Carcinoma

Endometrial cancer (also referred to as corpus uterine cancer or corpus cancer) is the most common female genital cancer in the developed world, with adenocarcinoma of the endometrium the most common type. ^[1]

In the United States, an estimated 3.1% of women will be diagnosed with this malignancy at some point in their lifetime. Approximately 69,120 new US cases of endometrial carcinoma are expected to have been diagnosed in 2025 (3.4% of all new US cancer cases), and about 13,860 women will die of this disease (2.2% of all cancer deaths). ^[2]

Endometrial cancer is often diagnosed at an early stage, largely because of the hallmark symptom of postmenopausal bleeding. ^[3]  Early diagnosis contributes to favorable survival outcomes. Nevertheless, death rates from uterine cancer in the United States have risen since 1997, with the highest mortality among non-Hispanic Black women. ^[4]

Multiple epidemiologic risk factors, as well as protective factors, have been identified in patients who have adenocarcinoma of the endometrium.

Risk factors

Endogenous factors

Endogenous factors are as follows:

• Obesity
• Nulliparity
• Late menopause (aged >52 years)

Unopposed estrogen

Unopposed estrogen, either as menopausal hormone therapy or endogenously produced (eg, granulosa cell tumor, polycystic ovary syndrome), increases the risk of endometrial cancer.

Obesity is known to increase endogenous estrogen because the presence of fat appears to be responsible for the conversion of androstenedione to estrogen compounds at a much higher rate than if fat is not present.

Anovulation, which may be secondary to unopposed estrogen, also appears to contribute to this effect.

Tamoxifen

Tamoxifen has been suggested by some studies to cause an increased incidence of adenocarcinoma of the endometrium. These data were derived from retrospective analyses in which adenocarcinoma of the endometrium was not an end point in multiple prospective randomized studies evaluating the role of tamoxifen in patients with breast cancer. ^[5]

A case control study using the Surveillance, Epidemiology, and End Results (SEER) database indicates that when confounding factors have been corrected, the risk of endometrial cancer does not appear to be increased in patients taking tamoxifen. ^[6] The results of this study are reassuring, particularly because of the prophylactic role of tamoxifen for women at increased risk for breast cancer.

A systematic review showed that tamoxifen raises the risk of endometrial carcinoma (mean relative risk, 2.25) compared with no treatment or raloxifene or aromatase inhibitor therapy. In some studies, the risk seemed to increase with the duration of therapy, and patients remained at elevated risk for at least 5 years after treatment. ^[7]

Associated medical conditions

Some associated medical conditions have been found to increase the incidence of endometrial cancer. Breast, colon, and ovarian cancers are frequently observed in women with endometrial cancer. Data suggest that women who have had breast cancer have a 2- to 3-fold increased risk of subsequently developing endometrial cancer.

Women who have hereditary nonpolyposis colon cancer (HNPCC; also referred to as Lynch syndrome) appear to have a markedly increased risk for developing endometrial cancer. Women with HNPCC account for only 2-10% of all female cases of colon cancer, but approximately 5% of all endometrial cancers occur in women with this risk factor. These women have a 27-60% lifetime risk of developing endometrial cancer, and the disease tends to occur at a younger age (46-54 years). The greatest risk of developing endometrial cancer in women with HNPCC occurs from age 40-60 years, at which time the absolute risk is greater than 1% per year.

Currently, no data indicate that annual screening of women with HNPCC will detect endometrial cancer at a sufficiently early stage to improve survival compared with those whose diagnosis is made when symptoms appear. Nevertheless, because of the high risk of endometrial cancer in these individuals and because of the potential life-threatening nature of this disease, HNPCC patients should be so informed and screening is certainly suggested. According to American Cancer Society guidelines, women with HNPCC should be offered screening with an endometrial biopsy by age 35 years.

Bjorge et al found that metabolic syndrome is associated with an increased risk of endometrial carcinoma and fatal uterine corpus cancer. Particularly in women with a high body mass index, the association appears to go beyond the risk conferred by obesity alone. ^[8]

Family history

Individuals with a family history of endometrial cancer appear to be at increased risk.

Phenotype characteristics

At one time, a classic phenotypic characteristic was thought to exist for a woman who would develop endometrial cancer. This phenotype included patients who were obese, nulliparous, and anovulatory in many instances. More recently, the existence of two pathogenic types of endometrial cancer was appreciated.

The first type occurs in women who fall into the classic category. These women are obese and have hyperlipidemia, signs of hyperestrogenism, uterine bleeding, infertility, and late onset of menopause. They may have hyperplasia of the ovary and endometrium. These patients tend to be White, obese, nulliparous, and have well-differentiated superficially invasive cancers that are sensitive to progesterone. They have a very favorable prognosis, and extrauterine disease is unusual in this group of patients. Fortunately, most women with endometrial cancer are in this category.

The second type occurs in women who have none of the disease states present in the classic presentation. These individuals tend to have poorly differentiated tumors, deep myometrial invasion, a high degree of metastasis to the lymph nodes and other sites, decreased sensitivity to progestins, and a poor prognosis. These patients tend to be thin, multiparous, and African American.

Protective factors

Combination oral contraceptives

Increasing data indicate that the use of combination oral contraceptives (OCs) decreases the risk of developing endometrial cancer. A longer duration of OC use is associated with a greater reduction in risk. ^[9]

Several studies have noted that women who use OCs at some time have a 0.5 relative risk of developing endometrial cancer compared with women who have never used OCs. This protection occurs in women who have used OCs for at least 12 months, and the protection continues for at least 10 years after OC use. Protection is most notable for nulliparous women.

Cigarette smoking

Smoking apparently decreases the risk of developing endometrial cancer. The effects of smoking are related to body weight. Heavier women who smoke have the greatest reduction in risk.

Women who smoke are known to undergo menopause 1-2 years earlier than women who do not smoke.

Although smoking apparently reduces the risk of developing early stages of endometrial cancer, this advantage is strongly outweighed by the increased risk of lung cancer and other major health problems associated with smoking.

United States statistics

SEER data from 2018-2022 cases reveal a total age-adjusted incidence of 28.3 cases per 100,000 women. The incidence in White women is 27.6 cases per 100,000 compared with the incidence in Black women, which is 30.6 cases per 100,000. ^[2]

Race- and age-related demographics

Mortality is higher in Black women (9.8 deaths per 100,000) than in White women (4.8 deaths per 100,000). Asian/Pacific Islander women have the lowest mortality (3.8 deaths per 100,000) among all racial and ethnic groups.

Endometrial adenocarcinoma occurs during the reproductive and menopausal years. The median age of women with this malignancy is 64 years; most patients are aged 55-64 years. ^[2]

Multiple prognostic factors exist for endometrial cancer. These prognostic factors generally are related to surgical pathologic findings. As in all cancers, the stage of the disease is the most important prognostic factor. Obviously, the surgical procedure helps determine the stage. Listed below are prognostic factors that may relate specifically to the stage of the disease and, thereby, may affect overall survival.

Prognostic factors - histopathologic subtypes

Most endometrial carcinomas are endometrioid adenocarcinomas. Adenoacanthomas (benign squamous components) and adenosquamous carcinoma (malignant squamous components) make up the next largest category.

Clear cell and papillary serous adenocarcinomas represent approximately 10% of all endometrial cancers and are considered to be poor histopathologic subtypes. These latter subtypes tend to have deeply invasive myometrial involvement, and they have a propensity for extrauterine spread, even though the myometrium may be superficially involved.

Previously, a patient with an adenosquamous carcinoma was thought to have a poor prognostic histotype because of the malignant squamous component.

Data suggest that irrespective of whether a squamous component is present (either benign or malignant), prognosis is related directly to the grade of the adeno component and not the fact that a squamous malignancy is present. If a malignant squamous component is present, a greater tendency exists for a more poorly differentiated adeno component to be present.

Considerable evidence suggests that carcinosarcomas are not true sarcomas, as it appears they are derived from an epithelial origin. As a result, carcinosarcomas are considered as a subset of endometrial cancers (type 2). ^[10]

Histologic differentiation

The degree of histologic differentiation of endometrial cancer has long been accepted as a sensitive indicator of prognosis. Patients with well-differentiated adenocarcinomas tend to have involvement of the endometrium or superficial myometrium, and extrauterine disease is unusual.

However, if a poorly differentiated lesion is present, these cancers tend to be much more aggressive, involving significant myometrial invasion, and often have extrauterine metastasis, either with positive peritoneal cytology, retroperitoneal spread, or involvement of the pelvic and/or para-aortic lymph nodes.

Because papillary and clear cell carcinomas are associated with a relatively poor prognosis, these subtypes are not usually graded but are considered in the same category as a poorly differentiated cancer.

Myometrial invasion

The degree of myometrial invasion continues to be a consistent indication of tumor virulence. As the depth of myometrial invasion increases, the chance of having extrauterine disease is greater.

As noted above, grade and depth of invasion, as a generalization, are interrelated. As the grade of the tumor increases, an increase usually occurs in the depth of myometrial invasion; however, exceptions exist in that a grade 1 lesion can have deep myometrial invasion and a grade 3 lesion can be limited to the endometrium.

When grade and depth of invasion are evaluated separately, the depth of invasion appears to be a more important prognostic factor than the grade of the tumor.

Peritoneal cytology

Cytologic evaluation of the peritoneum appears to be an important prognostic factor. Although no universal agreement has been reached about the significance of cytologic evaluation findings, the vast majority of data in the literature suggest that they represent an independent prognostic factor.

Cytologic evaluation findings also appear to correlate with other prognostic factors, such as depth of myometrial invasion and lymph node metastasis.

The International Federation of Gynecology and Obstetrics (FIGO) staging system states that positive cytology should be reported separately without changing the stage. If ascitic fluid is not present at the time of the exploratory laparotomy, a saline lavage of the pelvis and lower abdomen is performed and the specimen is submitted for cytologic evaluation.

Lymph node metastasis

A considerable number of patients who were thought to have clinical stage I endometrial cancer were, in fact, found to have lymph node metastasis when histopathologic evaluation was performed on the lymph nodes.

Again, a correlation among multiple prognostic factors has been shown to be present. Patients with poorly differentiated cancers, papillary serous and clear cell carcinomas, deep myometrial invasion, positive peritoneal cytology, or adnexal metastasis tend to have an increased risk of having lymph node metastasis.

Subsequent therapy after primary surgery depends on prognostic factors and spread of the disease. If the disease is limited to the uterus, surgery appears to be adequate treatment, with the possible exception of patients who have poorly differentiated deeply invasive myometrium. In these patients, data suggest that, possibly, postoperative irradiation may be of benefit. In patients who have disease outside of the uterus, radiation therapy may be effective; however, this has not been evaluated in a prospective randomized study. Most investigators irradiate the appropriate area if lymph node metastasis is present.

In patients with advanced disease (ie, intraperitoneal disease, disease outside of the peritoneal cavity), systemic chemotherapy may be of benefit. Studies suggest that carboplatin and paclitaxel are the drugs of choice when systemic chemotherapy is needed.

The 5-year relative survival for patients with uterine cancer is 81.1%. The survival by stage for uterine cancer from 2015-2021 is as follows ^[2] :

• Localized (confined to primary site; 67% of cases) - 95.1% 5-year relative survival

• Regional (spread to regional lymph nodes; 18% of cases) - 70% 5-year relative survival

• Distant (cancer has metastasized; 11% of cases) - 19.4% 5-year relative survival

• Unknown (unstaged; 4% of cases) - 58.8% 5-year relative survival

Increasingly, data suggest that lymphovascular space involvement in the myometrium predicts extant disease and a poor prognosis. Whether the poor prognosis remains when other prognostic factors are evaluated is less well defined.