Overview and Risk Factors

Cancer of the endometrium, the mucous membrane lining the uterus, makes up about 90% of uterine cancers. With approximately 40,000 cases annually, it is the most common gynecologic cancer in the United States. Epithelial and muscle cells of the uterus have potential for malignant transformation and constitute the 2 main histologic types of uterine cancer: adenocarcinoma and sarcoma. Adenocarcinoma, the most common uterine malignancy, will be the focus of this chapter.

Abnormal vaginal bleeding is the most common symptom of endometrial cancer, but a woman may also experience abdominal pain, dysuria, and/or dyspareunia. Vaginal bleeding in any postmenopausal woman should be considered uterine cancer until proven otherwise.

Type 1 endometrial carcinomas demonstrate a response to estrogen, whereas type 2 carcinomas do not. Because type 2 tumors lack well-identified risk factors, the following risk factors relate to type 1 endometrial carcinoma.

Risk Factors

Although endometrial cancer is more common in Caucasians, African Americans often have worse outcomes with the disease.¹

The following factors are also associated with risk:

• Obesity. A majority of patients diagnosed with endometrial cancer at a young age are obese.² Some studies have found that a high body mass index (BMI) and low physical activity were strong and independent risk factors for endometrial cancer.³ The relationship between obesity and cancer may be explained by obesity-related elevations in hormones and growth factors.⁴ Peripheral conversion of androgens to estrogen in adipose tissue leads to greater endogenous estrogen concentrations in obese persons.
• Age. Endometrial cancer risk increases with age, and the disease generally affects women over 50 years.
• Menopausal Estrogen Therapy. Unopposed estrogen increases risk for endometrial cancer. The combined use of estrogen and progestin is not associated with increased risk.
• Diabetes.
• Hypertension.
• Polycystic ovary syndrome (PCOS). Anovulation from PCOS or another cause results in persistent unopposed endogenous estrogen.
• Prolonged exposure to estrogen. Early menarche, late menopause, and nulliparity (especially when due to anovulation) possibly increase the risk for uterine malignancy.
• Genetics. A family history of hereditary nonpolyposis colorectal cancer greatly increases the risk of uterine carcinoma.
• Estrogen-secreting tumors or history of estrogen-responsive cancer.
• Decreased sex-hormone binding globulin levels.

Oral contraception, multiparity, and exercise are considered protective.

Diagnosis and Treatment

Diagnosis

The patient's medical history may reveal abnormal vaginal bleeding or discharge, in addition to nonspecific findings such as lower abdominal pain, dysuria, and dysparuenia. 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 should follow any Pap smear that shows endometrial cells, whether normal or atypical. It is a simple procedure. An exception may occur when normal endometrial cells are present and the woman is premenopausal and asymptomatic. Annual endometrial biopsy may be used to screen women with a personal or family history of hereditary nonpolyposis colorectal cancer gene mutations or an extensive family history of colon cancer.

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 is high.

Transvaginal ultrasound can measure the endometrial thickness, which should be less than 4 mm in a postmenopausal woman. Sonohysterography, which involves infusion of fluid into the uterus, may also help distinguish normal from abnormal endometrium.

Treatment

Endometrial cancer staging requires hysterectomy and bilateral salpingo-oophorectomy. Perioperative inspection of the opened uterus, along with clinical history, helps determine if 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 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:

I. Cancer only in body of uterus.
II. Cancer spread from uterus to cervix.
III. Cancer spread outside the uterus, but inside the pelvis; bladder and rectum are not affected; lymph nodes may be positive.
IV. Cancer involves bladder, rectum, or organ outside pelvis.

Cancer antigen (CA) 125 measured preoperatively helps predict whether cancer has spread beyond the uterus. However, it cannot be used as a screening tool or as a substitute for surgical staging.

Nutritional Considerations

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 seems to 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:

Eating less meat and fat. Studies found a 50% greater risk for endometrial cancer among women who consumed the greatest amount of processed meat and fish.⁵ Consumption of red meat and eggs is also associated with greater endometrial cancer risk.⁶

Higher intake of fat, particularly saturated fat, is associated with elevations of endometrial cancer risk on the order of 60% to 80%.^6,7 Some evidence indicates that this association is due to the influence of dietary fat on adiposity and, consequently, on circulating estrogens.

Fruits, vegetables, whole grains, and legumes. Although findings are limited, evidence suggests that vegetables, fruits, and the nutrients these foods contain (ie, vitamin C, various carotenoids, folate, phytosterols) are associated with reduced risk for endometrial cancer. The hypothesized risk reduction may be as high as 50% to 60%.^8,9

An inverse association between whole grain intake and endometrial cancer has been observed, although some data suggest that this benefit may be restricted to women who have never used hormones.¹⁰ Higher intakes of soy and other legumes may also decrease risk.⁶

Some whole grains and most legumes have a low glycemic index (a ranking of carbohydrate-containing foods, based on the food's effect on blood sugar compared with a standard reference food's effect). Women whose diets had the most high-glycemic-index foods had a roughly 50% greater risk for endometrial cancer than those whose diets had the lowest amount of these foods. Among obese women (BMI > 30), the risk for endometrial cancer in those eating the most high-glycemic-index foods was roughly 90% greater.¹¹ In nondiabetic women, those eating diets highest in glycemic load (glycemic index of a food times the number of grams of carbohydrates in the food serving) had a roughly 45% greater risk for endometrial cancer.¹²

Moderating alcohol consumption. Outcomes of studies on alcohol intake and risk for uterine cancers are conflicting, with various studies finding no association, a protective effect, or increased risk. Consistently high alcohol intake is associated with increased risk in young women (under age 50) and in African American women.^13,14

Orders

See Basic Diet Orders.

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.

References

1. Connell PP, Rotmensch J, Waggoner SE, Mundt AJ. Race and clinical outcome in endometrial carcinoma. Obstet Gynecol. 1999;94:713-720.

2. Soliman PT, Oh JC, Schmeler KM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol. 2005;105:575-580.

3. Schouten LJ, Goldbohm RA, van den Brandt PA. Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. J Natl Cancer Inst. 2004;96:1635-1638.

4. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11:1531-1543.

5. Zheng W, Kushi LH, Potter JD, et al. Dietary intake of energy and animal foods and endometrial cancer incidence. The Iowa women's health study. Am J Epidemiol. 1995;142:388-394.

6. Goodman MT, Hankin JH, Wilkens LR, et al. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res. 1997;57:5077-5085.

7. Littman AJ, Beresford SA, White E. The association of dietary fat and plant foods with endometrial cancer (United States). Cancer Causes Control. 2001;12:691-702.

8. McCann SE, Freudenheim JL, Marshall JR, Brasure JR, Swanson MK, Graham S. Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control. 2000;11:965-974.

9. Barbone F, Austin H, Partridge EE. Diet and endometrial cancer: a case-control study. Am J Epidemiol. 1993;137:393-403.

10. Kasum CM, Nicodemus K, Harnack LJ, et al. Whole grain intake and incident endometrial cancer: the Iowa Women's Health Study. Nutr Cancer. 2001;39:180-186.

11. Silvera SA, Rohan TE, Jain M, Terry PD, Howe GR, Miller AB. Glycaemic index, glycaemic load and risk of endometrial cancer: a prospective cohort study. Public Health Nutr. 2005;8:912-919.

12. Folsom AR, Demissie Z, Harnack L, and the Iowa Women's Health Study. Glycemic index, glycemic load, and incidence of endometrial cancer: the Iowa women's health study. Nutr Cancer. 2003;46:119-124.

13. Wise LA, Palmer JR, Harlow BL, et al. Risk of uterine leiomyomata in relation to tobacco, alcohol, and caffeine consumption in the Black Women's Health Study.
Hum Reprod. 2004;19:1746-1754.

14. Weiderpass E, Ye W, Mucci LA, et al. Alcoholism and risk for endometrial cancer. Int J Cancer. 2001;93:299-301.