Endometrial Cancer

Cancer of the endometrium is the most common gynecologic cancer in the United States, with over 60,000 new cases diagnosed annually.[1]

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.

Risk Factors

The main risk for developing endometrial cancer comes from prolonged exposure to excess endogenous or exogenous estrogen in the absence of opposition by progestin.[2] Common sources of endogenous estrogen include:

  • Obesity: Obesity accounts for > 50% of all cases of endometrial cancer,[3] presumably due to the peripheral conversion of androgens to estrogen in adipose tissue, which leads to greater endogenous estrogen concentrations in obese persons.[4] 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.[5] An obese woman with BMI ≥ 40 is seven times more likely to develop endometrial cancer compared with a normal-weight woman.[6] 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.[7]
  • Polycystic ovary syndrome (PCOS): Anovulation from PCOS or other causes results in persistent exposure to unopposed endogenous estrogen.[8]
  • Prolonged exposure to estrogen: Early menarche, late menopause, and nulliparity (especially when due to anovulation) may increase the risk for endometrial cancer.[9]
  • Estrogen-secreting tumors: Although rare, tumors that secrete estrogen increase the risk of endometrial carcinoma.[10]

Exogenous estrogen sources include:

  • Menopausal Estrogen Therapy. Estrogen therapy without progestin significantly increases the risk of endometrial cancer.[11]
  • Tamoxifen use. There is an increased risk in women using tamoxifen as therapy for breast cancer.[12]

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.[13]
  • 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.[14] ,[15]
  • Genetics: Women who have a first degree relative with endometrial cancer are at increased risk of developing endometrial cancer.[16] A family history of hereditary nonpolyposis colorectal cancer (Lynch Syndrome) greatly increases the risk as well.[17]

Protective Factors

Oral contraceptive use: Contraceptive pills containing progestin reduce the risk of endometrial cancer by about 30%.[18]

Exercise: Regular physical activity is associated with a 20%-30% reduction in risk.[19]

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 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).

Treatment

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:

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

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).[20] ,[21] 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.[22] 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.[23] 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%).[24] 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.

Previous research found that a higher fat intake, particularly saturated fat, was associated with elevations of endometrial cancer risk by approximately 60%-80%.[9],[25]

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.[26] 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,[27] previous studies suggested that these foods may be associated with reductions in risk of as much as 50%-60%.[28] ,[29] 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.[30]

A 2015 meta-analysis showed that a high soy intake is associated with a nearly 20% lower endometrial cancer risk.[31]

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.[32] 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. [21]

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.[33] Similarly, green tea drinkers had a nearly 20% lower risk for endometrial cancer in the highest compared with lowest intake group.[34] 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.[35]

Orders

See Basic Diet Orders Chapter

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).

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.  [PMID:26742998]
  2. Brinton LA, Berman ML, Mortel R, et al. Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol. 1992;167(5):1317-25.  [PMID:1442985]
  3. Reeves GK, Pirie K, Beral V, et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ. 2007;335(7630):1134.  [PMID:17986716]
  4. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1531-43.  [PMID:12496040]
  5. Zhang Y, Liu H, Yang S, Zhang J, Qian L, Chen X. Overweight, obesity and endometrial cancer risk: results from a systematic review and meta- analysis . Int J Biol Markers . 2014;29:e21–e29.
  6. Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol . 2013;31:2607–2618.
  7. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review 1975–2012. National Cancer Institute website. Available at: https://seer.cancer.gov . Updated November 18, 2015. Accessed July 13, 2017.
  8. Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod. 2012;27(5):1327-31.  [PMID:22367984]
  9. McPherson CP, Sellers TA, Potter JD, et al. Reproductive factors and risk of endometrial cancer. The Iowa Women's Health Study. Am J Epidemiol. 1996;143(12):1195-202.  [PMID:8651218]
  10. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol. 2003;21(6):1180-9.  [PMID:12637488]
  11. Persson I, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ. 1989;298(6667):147-51.  [PMID:2538173]
  12. Sismondi P, Biglia N, Volpi E, Giai M, de Grandis T. Tamoxifen and endometrial cancer. Ann N Y Acad Sci . 1994;734:310–321.
  13. Connell PP, Rotmensch J, Waggoner SE, et al. Race and clinical outcome in endometrial carcinoma. Obstet Gynecol. 1999;94(5 Pt 1):713-20.  [PMID:10546716]
  14. Furberg AS, Thune I. Metabolic abnormalities (hypertension, hyperglycemia and overweight), lifestyle (high energy intake and physical inactivity) and endometrial cancer risk in a Norwegian cohort. Int J Cancer. 2003;104(6):669-76.  [PMID:12640672]
  15. Friberg E, Orsini N, Mantzoros CS, et al. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007;50(7):1365-74.  [PMID:17476474]
  16. Lucenteforte E, Talamini R, Montella M, et al. Family history of cancer and the risk of endometrial cancer. Eur J Cancer Prev. 2009;18(2):95-9.  [PMID:19337055]
  17. Kwon JS, Scott JL, Gilks CB, et al. Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol. 2011;29(16):2247-52.  [PMID:21537049]
  18. Mueck AO, Seeger H, Rabe T. Hormonal contraception and risk of endometrial cancer: a systematic review. Endocr Relat Cancer. 2010;17(4):R263-71.  [PMID:20870686]
  19. Cust AE, Armstrong BK, Friedenreich CM, Slimani N, Bauman A. Physical activity and endometrial cancer risk: a review of the current evidence, biologic mechanisms and the quality of physical activity assessment methods. Cancer Causes Control . 2007;18:243–258.
  20. Si CJ, Shu L, Zheng PF, et al. Dietary patterns and endometrial cancer: a meta-analysis. Eur J Cancer Prev. 2017;26(4):336-345.  [PMID:27139775]
  21. Nagle CM, Olsen CM, Ibiebele TI, et al. Glycemic index, glycemic load and endometrial cancer risk: results from the Australian National Endometrial Cancer study and an updated systematic review and meta-analysis. Eur J Nutr. 2013;52(2):705-15.  [PMID:22648201]
  22. Faramawi MF, Johnson E, Fry MW, et al. Consumption of different types of meat and the risk of renal cancer: meta-analysis of case-control studies. Cancer Causes Control. 2007;18(2):125-33.  [PMID:17242980]
  23. Genkinger JM, Friberg E, Goldbohm RA, et al. Long-term dietary heme iron and red meat intake in relation to endometrial cancer risk. Am J Clin Nutr. 2012;96(4):848-54.  [PMID:22952183]
  24. Zhao J, Lyu C, Gao J, et al. Dietary fat intake and endometrial cancer risk: A dose response meta-analysis. Medicine (Baltimore). 2016;95(27):e4121.  [PMID:27399120]
  25. Littman AJ, Beresford SA, White E. The association of dietary fat and plant foods with endometrial cancer (United States). Cancer Causes Control. 2001;12(8):691-702.  [PMID:11562109]
  26. Ganmaa D, Cui X, Feskanich D, et al. Milk, dairy intake and risk of endometrial cancer: a 26-year follow-up. Int J Cancer. 2012;130(11):2664-71.  [PMID:21717454]
  27. Kabat GC, Park Y, Hollenbeck AR, et al. Intake of fruits and vegetables, and risk of endometrial cancer in the NIH-AARP Diet and Health Study. Cancer Epidemiol. 2010;34(5):568-73.  [PMID:20619761]
  28. McCann SE, Freudenheim JL, Marshall JR, et al. Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control. 2000;11(10):965-74.  [PMID:11142531]
  29. Barbone F, Austin H, Partridge EE. Diet and endometrial cancer: a case-control study. Am J Epidemiol. 1993;137(4):393-403.  [PMID:8460621]
  30. McCullough ML, Bandera EV, Patel R, et al. A prospective study of fruits, vegetables, and risk of endometrial cancer. Am J Epidemiol. 2007;166(8):902-11.  [PMID:17690222]
  31. Zhang GQ, Chen JL, Liu Q, et al. Soy Intake Is Associated With Lower Endometrial Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies. Medicine (Baltimore). 2015;94(50):e2281.  [PMID:26683956]
  32. Inoue-Choi M, Robien K, Mariani A, et al. Sugar-sweetened beverage intake and the risk of type I and type II endometrial cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2013;22(12):2384-94.  [PMID:24273064]
  33. Zhou Q, Luo ML, Li H, et al. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies. Sci Rep. 2015;5:13410.  [PMID:26302813]
  34. Zhou Q, Li H, Zhou JG, et al. Green tea, black tea consumption and risk of endometrial cancer: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016;293(1):143-55.  [PMID:26138307]
  35. Friberg E, Orsini N, Mantzoros CS, et al. Alcohol intake and endometrial cancer risk: a meta-analysis of prospective studies. Br J Cancer. 2010;103(1):127-31.  [PMID:20485288]

Last updated: July 16, 2018