Cancer of the endometrium is the most common gynecologic cancer in the United States, with over 60,000 new cases diagnosed annually.
Endometrial cancers can be divided into two sub-types: Type 1, which are estrogen dependent and comprise about 80% of all endometrial cancers, and Type 2, which are non-estrogen dependent. Type 1 endometrial cancers are the subject of this chapter.
Abnormal vaginal bleeding is the most common symptom, but a woman may also experience discharge, weight loss, abdominal or pelvic pain, dysuria, or dyspareunia. Vaginal bleeding in any postmenopausal woman should be considered uterine cancer until proven otherwise.
Most endometrial cancers are slow-growing and are discovered at an early stage. These cases can be successfully treated, usually by hysterectomy, with better than 90% cure rates. Advanced cases that spread beyond the uterus are often fatal.
The main risk for developing endometrial cancer comes from prolonged exposure to excess endogenous or exogenous estrogen in the absence of opposition by progestin. Common sources of endogenous estrogen include:
- Obesity: Obesity accounts for > 50% of all cases of endometrial cancer, presumably due to the peripheral conversion of androgens to estrogen in adipose tissue, which leads to greater endogenous estrogen concentrations in obese persons. Compared with normal-weight women, obese women have a much greater risk of being diagnosed with endometrial cancer, which rises progressively with higher body weight. An obese woman with BMI ≥ 40 is seven times more likely to develop endometrial cancer compared with a normal-weight woman. The increased incidence of obesity in recent decades has increased endometrial cancer diagnoses in women aged < 50 years by 2% each year from 1992-2012.
- Polycystic ovary syndrome (PCOS): Anovulation from PCOS or other causes results in persistent exposure to unopposed endogenous estrogen.
- Prolonged exposure to estrogen: Early menarche, late menopause, and nulliparity (especially when due to anovulation) may increase the risk for endometrial cancer.
- Estrogen-secreting tumors: Although rare, tumors that secrete estrogen increase the risk of endometrial carcinoma.
Exogenous estrogen sources include:
- Menopausal Estrogen Therapy. Estrogen therapy without progestin significantly increases the risk of endometrial cancer.
- Tamoxifen use. There is an increased risk in women using tamoxifen as therapy for breast cancer.
Other risk factors include:
- Age: Risk increases with age. The disease primarily affects women over age 50.
- Race: Although endometrial cancer is more common in whites, blacks often have worse outcomes from the disease.
- Diabetes and hypertension: Women with hypertension and diabetes (particularly type 2) have an increased risk for endometrial cancer, which may reflect the presence of common risk factors such as obesity. ,
- Genetics: Women who have a first degree relative with endometrial cancer are at increased risk of developing endometrial cancer. A family history of hereditary nonpolyposis colorectal cancer (Lynch Syndrome) greatly increases the risk as well.
Oral contraceptive use: Contraceptive pills containing progestin reduce the risk of endometrial cancer by about 30%.
Exercise: Regular physical activity is associated with a 20%-30% reduction in risk.
The patient’s medical history may reveal abnormal vaginal bleeding or discharge in addition to nonspecific findings, such as lower abdominal pain, dysuria, and dyspareunia. Pelvic exam may reveal uterine enlargement but cannot distinguish whether it is benign or malignant. An incidental Pap smear finding of either normal or atypical endometrial cells increases the chance of a uterine cancer diagnosis. However, a normal Pap result does not rule out endometrial cancer.
Endometrial biopsy is indicated in any postmenopausal woman with vaginal bleeding and should follow any Pap smear that shows endometrial cells, whether normal or atypical, because the mere presence of endometrial cells may be a sign of endometrial pathology. Biopsy may not be necessary in asymptomatic premenopausal women.
Hysteroscopy or dilation and curettage can also provide endometrial tissue samples, but these procedures are far more invasive, require anesthesia, and have more frequent complications compared with endometrial biopsy. Although it is the preferred procedure for diagnosis, hysteroscopy can be reserved for cases in which endometrial biopsy is inconclusive, but the pre-test probability for cancer is high.
Transvaginal ultrasound can measure the endometrial thickness, which should be less than 4 mm in a postmenopausal woman. Annual endometrial biopsy may be used to screen women with a personal or family history of hereditary nonpolyposis colorectal cancer gene mutations (Lynch syndrome).
Endometrial cancer staging requires hysterectomy and bilateral salpingo-oophorectomy. Perioperative inspection of the opened uterus, along with clinical history, helps determine whether lymphadenectomy is required. Selective lymphadenectomy reduces associated morbidity and mortality. Peritoneal fluid cytology should be obtained during surgery for purposes of staging.
Surgical cytoreduction, radiation, hormone therapy, and chemotherapy may all be part of a treatment regimen. Progestin therapy without hysterectomy may be used in women with the lowest stage or grade of disease who would like to preserve their fertility.
The International Federation of Gynecology and Obstetrics defines the following stages of endometrial cancer:
- Cancer only in body of uterus.
- Cancer spread from uterus to cervix.
- Cancer spread outside the uterus but inside the pelvis; bladder and rectum are not affected; lymph nodes may be positive.
- Cancer involves bladder, rectum, or organ outside pelvis.
As with many cancers, the risk for uterine cancers appears to be associated with greater intakes of foods found in Western diets (animal products, refined carbohydrates). , Risk may be lower among women whose diets are high in fruits, vegetables, whole grains, and legumes. The lower risk in persons eating plant-based diets may be related to a reduced amount of free hormones circulating in the blood or to a protective effect of micronutrients found in these diets.
The following factors are under study for possible protective effects:
Avoiding or Reducing Meat, Dairy Products, and Saturated Fat. The associations between meat and endometrial cancer have not been consistent; overall, case-control studies have identified increased risk of endometrial cancer associated with red meat in particular, a finding not reflected in most prospective studies. However, connections have emerged between components of meat (heme iron and saturated fat) and this cancer. The Swedish Mammography Cohort found significant relationships between both heme iron (found in both red and white meat) and liver consumption and endometrial cancer. A dose-response analysis of fat intake and endometrial cancer concluded that increasing total fat intake by 10% of calories increased risk for this cancer by 5%. However, increasing saturated fat intake by 10g/1,000 kcals was associated with a much greater risk (17%). This implies that the effect of saturated fats on increasing risk for endometrial cancer is more than three times that of other types of fat.
Dairy products may contribute to these effects, as shown in the Nurses’ Health study, which found a 40% greater risk for endometrial cancer in postmenopausal non-users of hormone replacement therapy (HRT) who consumed 3 or more dairy servings per day, compared with those consuming less than one. Some evidence indicates that this association is due to the influence of dietary fat on adiposity and, consequently, on circulating estrogens.
Fruits, Vegetables, and Legumes. Although the NIH-AARP study found no significant relationship between fruit and vegetable intakes and endometrial cancer, previous studies suggested that these foods may be associated with reductions in risk of as much as 50%-60%. , In the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort of over 41,000 women, protective effects of vegetables and fruits (20% and 25% lower risk, respectively, for those consuming the highest amounts of these foods) were identified only in women who had both never used hormone therapy.
A 2015 meta-analysis showed that a high soy intake is associated with a nearly 20% lower endometrial cancer risk.
Avoidance of Sugar and High Glycemic-Index Carbohydrates. The Iowa Women’s Health Study found a 78% greater risk for endometrial cancer in women who consumed the most sugar-sweetened beverages, compared to those who consumed the lowest amount. A meta-analysis comparing women whose diets had the highest compared with the lowest glycemic load found a roughly 20% higher risk for those in the former category. 
Coffee and Green Tea Drinking. Women who consume the most coffee were found to have a 20% lower risk for endometrial cancer when compared to those who consumed the lowest amount, and high coffee consumers who had never been treated with HRT were found to have a 40% lower risk. Similarly, green tea drinkers had a nearly 20% lower risk for endometrial cancer in the highest compared with lowest intake group. These effects may be due to the ability of caffeine and other methylxanthines in coffee to increase sex hormone-binding globulin (SHBG) and increase insulin sensitivity; for green tea, actions may include promotion of apoptosis, cell cycle arrest, up-regulation of glutathione- S-transferases that inactivate carcinogens, and anti-estrogen effects.
Moderating Alcohol Consumption. There appears to be a J-shaped relationship between ethanol consumption and risk for endometrial cancer. Women who consume between one-half and one drink per day were found to have a 4%-7% lower risk, while women who drank two and a half or more than 2.5 servings per day had a 14% and 25% greater risk, respectively, compared with nondrinkers or those who drank only occasionally.
Regular physical activity
Maintain a healthy weight
What to Tell the Family
The 5-year survival rate for uterine cancers is high, particularly with early detection and treatment. The family may support the patient’s adherence to diet and exercise recommendations by adopting the same practices, which are likely to improve their health as well. Some evidence suggests that following a low-fat, plant-based diet, maintaining a healthy weight, and getting regular exercise may reduce the risk of this disease.
Genetic counseling should be considered for family members of patients diagnosed with endometrial cancer who have a strong family history of endometrial cancer or colon cancer (Lynch syndrome).
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