The Epidemiology of Endometrial Cancer
Authors
INTRODUCTION
Incidence
Endometrial cancer is the fourth most common cancer among women in the United States and the most frequently diagnosed gynecologic malignancy. It is estimated that 46,470 American women will be diagnosed with the disease in 2011, accounting for 6% of new cancer cases.1 In other words, a woman born in the United States in 2011 has a lifetime risk of 1 in 39 of developing endometrial cancer.1, 2 Worldwide, it is anticipated that more than 287,000 women will be diagnosed with the disease in 2011.3
TRENDS
A significant increase in the incidence of endometrial cancer occurred in North America between 1960 and 1975. This has been widely interpreted to be a result of the marked increase in exogenous estrogen use for hormone replacement therapy in postmenopausal women. For example, during the decade between 1960 and 1970, the sale of oral estrogen preparations tripled in the United States, reaching an estimated peak of 17 million prescriptions a year.4 However, in the early 1980s the incidence rates returned to prior levels and have remained steady.5, 6 This decrease has largely been attributed to the inclusion of progestins in hormone replacement therapy regimens.6
PATHOGENESIS
It has been proposed that there are two types of endometrial cancer: estrogen dependent (type I) and estrogen independent (type II).7 Approximately 85% of endometrial cancers are type I. These cancers tend to occur in obese women and are typically preceded by complex atypical hyperplasia. Additionally, they are most commonly low grade endometrioid histology and confined to the uterus with minimal invasion. In contrast, type II tumors are more likely to occur in thin, older patients with an atrophic endometrium. Their histology is typically high grade serous or clear cell, and patients commonly have early metastasis.8, 9, 10 Approximately half of all endometrial cancer relapses occur in patients with type II tumors.10
There are also distinctions to be made between these two groups on a molecular level. For example, type I tumors commonly have PTEN, K-ras, and β-catenin mutations as well as microsatellite instability (MSI). Progesterone receptors are more likely to be found in significant numbers in these cancers. Type II tumors, on the other hand, typically have p53 mutations and HER2/neu amplification.8, 10 Table 1 outlines some of the differences between type I and type II endometrial cancers.
Table 1 Typical features of type I and type II endometrial cancers
| Type I | Type II |
| Grade | Low | High |
| Histology | Endometrioid | Serous or clear cell |
| Stage at diagnosis | I or II | III or IV |
| Molecular alterations | PTEN, MSI, β-catenin | HER2/neu, p53 |
DEMOGRAPHIC PATTERNS
Age
The majority of women diagnosed with endometrial cancer are peri- or postmenopausal between the ages of 50 and 65.6 The average age at diagnosis is 61.2 However, the risk of developing endometrial cancer increases with advancing age. For example, a woman under the age of 40 has a 1 in 1423 risk of developing the disease, but a woman older than 70 has a 1 in 81 risk.1As detailed in Table 2, in the United States, more than 40% of endometrial cancers are diagnosed in women older than 65.
Table 2 Percentage of endometrial cancer cases by age2
| Age (years) | % |
| <20 | 0 |
| 20–34 | 1.6 |
| 35–44 | 6.1 |
| 45–54 | 19.2 |
| 55–64 | 31.8 |
| 65–74 | 22.1 |
| 75–84 | 14.2 |
| ≥85 | 4.8 |
Race/ethnicity and geographic considerations
In the United States, white women are more likely to be diagnosed with endometrial cancer than African-American, Asian, or Hispanic women.6 The age-adjusted incidence rate for white women is 24.8 per 100,000 women, whereas it is 20.9, 18.2, and 15.9 for African-American, Asian, and Hispanic women, respectively.2 However, African-American women have a higher mortality rate than the other racial groups at 7.2 per 100,000 women, compared with 3.9 for white women, 2.5 for Asian women, and 3.0 for Hispanic women.2 In general, African-American women are more likely to present with regional or distant metastasis, have high-risk tumor types, have less access to care, and have more medical comorbidities than other racial groups.1, 6, 10
When incidence data from other parts of the world for endometrial cancer are studied, a number of observations can be made.11 In general, the incidence is highest in developed countries. For example, the incidence of endometrial cancer is much higher in North America, Australia, and Europe than in Central and South America, Asia, and Africa.6, 12, 13
Interestingly, when one compares among various regions within racial groups, there are differences noted in incidence rates. For example, studies have shown that the rates of endometrial cancer in African-American and Asian women living in the United States are higher than in women living in Africa or Asia.6 Additionally, there are data to suggest that Chinese and Japanese immigrants to the United States have a higher risk of endometrial cancer than women who remain in China and Japan.13 This suggests that environmental factors play an important role in the development of endometrial cancer. Other variables that may explain regional variations in incidence rates include registration deficiencies as well as differences in risk factors, such as obesity rates, among populations.6, 10
RISK FACTORS
Table 3 reviews common risk factors for endometrial cancer and their associated relative risk. It should be noted that the majority of these risk factors are related to excess estrogen, and are therefore applicable to type I tumors. The most common risk factor for type II cancers is age.10
Table 3 Risk factors associated with endometrial cancer8, 12
| Risk factor | Relative risk |
| Unopposed estrogen therapy | 10–20 |
| Estrogen-producing tumors | >5 |
| Tamoxifen | 2.5–7 |
| Obesity | 2–5 |
| Nulliparity/infertility | 2–3 |
| Diabetes mellitus | 2–3 |
| Menstrual factors | 1.5–3 |
Unopposed estrogen therapy
The first cases of endometrial cancer related to estrogen replacement therapy were reported in the 1960s.14 Since then, there have been many studies that have found an increased risk of endometrial carcinoma among patients receiving unopposed estrogen replacement therapy for menopausal symptoms.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Additionally, the longer a woman uses estrogen replacement, the higher her risk of developing endometrial cancer.6, 15, 29, 30, 31 Though it is generally thought to require 2–3 years of unopposed estrogen use to develop an increased risk of endometrial cancer, some studies have found up to a 40% increase in risk over baseline after only 1 year of estrogen use.25 It has also been noted that the risk of developing endometrial cancer increases with increased estrogen dose.29, 31
The increased risk of endometrial cancer persists after cessation of unopposed estrogen use, though the exact amount of time required for the risk to decrease to that of nonestrogen users is unclear. Some authors have reported a relatively rapid decrease in risk of cancer after cessation, while others have found an increased risk up to 10 years after cessation of estrogen use.22, 25, 29, 30 Mode of estrogen administration has also been evaluated, but found to be less important than the duration of estrogen use and the interval since it was last used.32
Significant differences in the biologic and clinical behavior of endometrial carcinoma among estrogen users and nonusers have been described. Cancers associated with estrogen use include a preponderance of well-differentiated, localized tumors, with a low incidence of myometrial invasion and metastases, and a 5-year survival rate of well over 90%.12, 33, 34 This likely explains why mortality from endometrial cancer did not increase when the incidence rate increased in 1960s and 1970s, and is in agreement with the theory that type I tumors are estrogen driven with a favorable prognosis.
Tamoxifen
Tamoxifen is a selective estrogen receptor modulator (SERM) that has antiestrogenic properties in breast tissue. As such, it is currently used to treat estrogen receptor-positive breast cancer. However, the drug has estrogen effects in other tissues, including the endometrium. In 1985, the first cases of endometrial carcinoma related to tamoxifen use were reported.35 Since then, multiple authors have confirmed this relationship.36, 37 Additionally, the risk of developing endometrial cancer increases with longer duration of tamoxifen use and higher cumulative dose of the drug.12, 38
There are conflicting data regarding the prognosis for patients who develop endometrial cancer while using tamoxifen. There is some evidence to suggest that long-term tamoxifen use (generally defined as 60 months or more) is associated with more high risk histologic types of endometrial cancer, such as grade 3 endometrioid, serous, and clear cell.39 Secondary to this, it has been argued that long-term tamoxifen users have a poorer prognosis when they develop endometrial cancer.40, 41 Contrarily, other studies have demonstrated that the majority of patients using tamoxifen have early-stage disease and grade one or two histology.37 To date, the majority of studies on this subject have failed to show a difference in survival between tamoxifen users and nonusers.37, 42, 43
Most importantly, the survival benefit offered to breast cancer patients by tamoxifen outweighs the potential risk of developing endometrial cancer. Additionally, no screening for endometrial cancer is recommended in patients currently taking tamoxifen. However, a high index of suspicion should be exercised in women on tamoxifen with complaints of abnormal vaginal bleeding.44
Obesity
Obesity, long recognized as an important risk factor for endometrial cancer, has been shown to increase exposure of the endometrium to endogenous estrogen in a number of ways. These include up to a 5-fold increase in the rate of peripheral conversion of estrogen precursors to active estrogen, increased 16α-hydroxylation of estrone (a biologically more active form), and increased serum levels of free estrogen due to decreased levels of serum sex being globulin.45, 46
As a risk factor for endometrial cancer, obesity has been reported to account for 17–46% of all cases.10, 12, 47 The heaviest women are at the highest risk of developing endometrial cancer.48, 49 A recent study found that overweight women had twice the risk of developing disease as normal-weight women, while obese women carried four to five times the risk.50 Brinton et al. reported that women with a body mass index (BMI) of 32 kg/m2 or greater were four times as likely to develop endometrial cancer as women with a BMI of less than 23 kg/m2, while women with a BMI of 35 kg/m2 or greater had six times the risk.51 Additionally, there are some data to suggest that for each 5 kg/m2 increase in BMI, there is a significant increase in risk of developing endometrial cancer.52
Multiple authors have reported that a patient’s current weight and her weight gain throughout adulthood are most predictive of her risk of developing endometrial cancer.48, 53 Larger weight gains over a woman’s life have also been reported to increase her risk.48 Additionally, the length of time a woman remains overweight affects her chance of developing cancer and at what age. Lu et al. noted that patients who reported 35% or more weight gain in their 20s were diagnosed with endometrial cancer 10 years earlier than women who reported a 5% or less weight change in their 20s. In this same study, women who remained overweight throughout their adulthood were five times more likely to develop endometrial cancer than their normal-weight counterparts.50
There have been some studies noting that elevated BMI is associated with less aggressive endometrial cancers. Mauland et al. reported more stage I and II cancers in obese women with a trend towards improved prognosis in these patients.54 However, it should be noted that the risk of cancer-related death is highest among morbidly obese women.55 Additionally, morbidly obese women have a greater risk of mortality due to causes other than their cancer.56
Nulliparity/infertility
A positive association between nulliparity and endometrial cancer was first recognized in the 1950s.6 Studies since then have found that nulliparous women have two to three times the risk of developing endometrial cancer compared with parous women.49 Moreover, a woman’s endometrial cancer risk decreases with each child she has.49, 57 Most studies have found no association between age at first birth and endometrial cancer. However, there is evidence that older age at last birth decreases the risk, with one study noting a relative risk of 0.3 for women who delivered their last child after the age of 40.57
Though nulliparity can be a manifestation of infertility, there is evidence that they are independent risk factors for developing endometrial cancer.58 Infertile women have been found to have 3.5 times more risk than fertile women for developing disease.49 Few studies have examined how infertility treatments alter a woman’s endometrial cancer risk.
Diabetes mellitus
An increased incidence of diabetes mellitus among patients with endometrial cancer has been described for many years.59 However, given the strong association between obesity and type 2 diabetes, and that many patients with endometrial cancer are obese, the proposed relationship between diabetes and endometrial cancer was often attributed to confounding. Multiple authors have since established type 2 diabetes to be an independent risk factor for developing endometrial cancer. These studies found a persistent elevated risk of developing endometrial cancer in diabetic patients when either adjusting for weight or studying nonobese women.53, 60, 61 Additionally, there is evidence that obese diabetic women have the highest risk of developing disease.62, 63
Recently, there has been increasing interest in insulin resistance and endometrial cancer, with multiple studies suggesting a relationship between the two.64, 65, 66 In one study, 66% of patients were noted to have insulin resistance at the time of their endometrial cancer diagnosis. Interestingly, half of the insulin-resistant woman did not have a history of diabetes.64 Another study that excluded diabetics, noted 35% of their subjects with endometrial cancer to have insulin resistance.66 Further work is needed to detail the exact role of insulin resistance in endometrial cancer development.
Menstrual history
Early menarche, defined as less than 11 or 12 years of age, has been noted to be associated with endometrial cancer in several studies.49, 67 The effect of early menarche on endometrial cancer is greater in younger women.49 This may be secondary to more accurate recall of menarche age in younger women.6
Conversely, late menopause has been described as a risk factor by multiple investigators.47, 68 MacMahon reported that women under the age of 52 who undergo menopause have twice the risk of developing endometrial cancer as women who undergo menopause under the age of 49.69 These findings have been confirmed by other authors.61
Menstruation span, defined as the number of years between menarche and menopause excluding pregnancy, has also been evaluated as a risk for endometrial cancer. Most authors have concluded that longer menstruation span is associated with more risk.70
Estrogen-producing tumors
An association between estrogen-producing tumors and endometrial cancer was first reported by Schroeder in 1922.71 Since then, studies of relatively large numbers of patients have found that between 6 and 10% of patients with estrogen-producing tumors will develop endometrial cancer.72, 73 However, autonomous estrogen-secreting ovarian tumors are a relatively rare cause of endometrial hyperplasia and carcinoma.
Polycystic ovary syndrome
A relationship between endometrial cancer and polycystic ovary syndrome (PCOS) was first suggested in the 1940s and 1950s.74 Since then, several authors have confirmed these findings with some studies reporting up to 30% of premenopausal endometrial cancer patients also having PCOS.6, 75 It was assumed that elevated endogenous estrogen in PCOS patients led to endometrial cancer. However, obesity and insulin resistance were not fully recognized as potential risk factors for endometrial cancer at the time many of these studies were performed. Given that many women with PCOS are obese and have insulin resistance, it is unclear if PCOS is truly an independent risk factor. A recent study suggests women under 50 years old with PCOS have four times the risk of endometrial cancer compared with controls. An increased risk remained when the authors controlled for BMI. However, there was no adjustment made for insulin resistance.76
Lynch syndrome
Approximately 5% of endometrial cancer cases can be attributed to an inherited predisposition.77 The majority of these cases are secondary to Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The syndrome is inherited in an autosomal dominant pattern with mutations in one of the DNA mismatch repair genes (MLH 1, MSH 2, MSH 6, or PMS 2), and is associated with colon, rectal, ovarian, small bowel, renal pelvis, ureteral, and endometrial cancers. Importantly, individuals with Lynch syndrome are at risk for developing more than one primary cancer over their lifetime.
Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer. Additionally, they typically develop endometrial cancer at an earlier age than the general population, with the mean age at diagnosis being 50.10 In fact, approximately 10% of women diagnosed with endometrial cancer under the age of 50 have Lynch syndrome.10 There are currently limited data regarding endometrial cancer prognosis for these women, but many authors believe that it is the same as for the general population.78, 79
Given their propensity for developing other malignancies and the risk of having family members with the same mutation, it is important to identify patients with Lynch syndrome. Of note, approximately 50% of Lynch syndrome patients diagnosed with both endometrial and colon cancer were diagnosed with endometrial cancer first.80 The Society of Gynecologic Oncologists (SGO) has published guidelines to aid with determining which patients should be screened for Lynch syndrome (Table 4).
Table 4. Society of Gynecologic Oncologists guidelines for genetic risk assessment for Lynch syndrome81
|
|
|
| Patients with endometrial or colorectal cancer diagnosed before age 50 Patients with endometrial or ovarian cancer with synchronous or metachronous Lynch-associated malignancies Patients with colorectal or endometrial cancer and more than two first degree relatives with a Lynch-associated malignancy Patient with a first or second degree relative meeting the above criteria | Patients meeting Amsterdam criteria Patients with synchronous or metachronous colorectal and ovarian or endometrial cancers Patients with a first or second degree relative with a known MMR mutation |
| Patients with one of the above criteria have a 5–10% chance of Lynch syndrome | Patients with one of the above criteria have a 20–25% chance of Lynch syndrome |
There are currently no clear data on how to screen women with Lynch syndrome for endometrial cancer. Expert opinion has generally recommended that these patients should receive annual endometrial biopsies and transvaginal ultrasounds once they reach the age of 30–35.82 Additionally, there are data that prophylactic hysterectomy and bilateral salpingo-oophorectomy significantly reduce the risk of endometrial cancer for Lynch syndrome patients.83 Therefore, this procedure should be offered once childbearing is complete.
PROTECTIVE FACTORS
Cigarette smoking
The inverse relationship between cigarette smoking and endometrial cancer risk has been known since the late 1970s.84, 85, 86, 87 Multiple authors have reported the relative risk of endometrial cancer to be 0.5 in smokers.12 The decreased risk is more pronounced among postmenopausal women.88 Additionally, the longer and heavier the duration of smoking, the less the risk for developing endometrial cancer. This association does not appear to be true for passive smokers.89 The biologic mechanism for these findings is unclear, but is likely related to alterations in endogenous hormones or metabolites.42 It should be emphasized, however, that the protection conferred by smoking is far outweighed by the many serious and well-documented health risks associated with tobacco use.
Contraceptive use
Combined oral contraceptive pills (OCPs) are known to be protective against endometrial cancer with the amount of risk reduction being proportional to the length of OCP use.49 It has been suggested that 5 years of oral contraceptive use will halve the risk of developing endometrial cancer.90 This protective effect is greatest in nulliparous women.49 Additionally, the risk reduction persists after discontinuation of OCPs, though the specific amount of time is unknown. Authors have found from 3 to 20 years of continued protection after OCPs were discontinued.91, 92, 93
There is also some evidence that the intrauterine device (IUD) use may also be associated with decreased risk.94 One study noted that women who had ever used an IUD had an odds ratio of 0.37 to develop endometrial cancer.95 Further studies are warranted, specifically those addressing levonorgestrel-containing IUDs.
CONCLUSIONS
Endometrial cancer is a very common malignancy affecting hundreds of thousands of women worldwide with the number of cases increasing annually. Understanding the epidemiology of this disease may not only aid with treatment, but also further the development of prevention strategies.
REFERENCES
Siegel, R., et al., Cancer statistics, 2011. The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer Journal for Clinicians, 2011. 61(4): p. 212-236. |
|
Howlader, N., et al. SEER Cancer Statistics Review, 1975-2008. 2011 [cited 2011; based on November 2010 SEER data submission]. Available from: http://seer.cancer.gov/csr/1975_2008/ |
|
Jemal, A., et al., Gobal Cancer Statistics. CA: A Cancer Journal for Clinicians, 2011. 61(2): p. 69-90. |
|
Weiss, N.S., D.R. Szekely, and D.F. Austin, Increasing incidence of endometrial cancer in the United States. New England Journal of Medicine, 1976. 295(23): p. 1259-1262. |
|
Duong, L.M., et al., Trends in endometrial cancer incidence rates in the United States, 1999-2006. Journal of Women's Health, 2011. 20(8): p. 1-7. |
|
Purdie, D.M. and A.C. Green, Epidemiology of endometrial cancer. Best Practice and Research in Clinical Obstetrics and Gynaecology, 2001. 15(3): p. 341-354. |
|
Bokhman, J.V., Two pathologic types of endometrial carcinoma. Gynecologic Oncology, 1983. 15(1): p. 10-17. |
|
Iglesias, D.A., et al., Chapter 6 - Endometrial Hyperplasia and Carcinoma., in Gynecologic Oncology: Clinical Practice and Surgical Atlas, 1st Edition, B. Karlan, R. Bristow, and A. Li, Editors. 2011, McGraw-Hill. |
|
Deligdisch, L. and C.F. Holinka, Endometrial carcinoma: two diseases? Cancer Detection and Prevention, 1987. 10(3-4): p. 237-246. |
|
McMeekin, D.S., et al., Chapter 23. Corpus: Epithelial Tumors, in Principles and Practice of Gynecologic Oncology, 5th Edition, R.R. Barakat, et al., Editors. 2009, Lippincott Williams & Wilkins: Baltimore. p. 683-686. |
|
Dunn, J.E., Jr., Geographic considerations of endometrial cancer. Gynecologic Oncology, 1974. 2(2-3): p. 114-121. |
|
Brinton, L.A., J. Lacey, J.V., and M.E. Sherman, Chapter 1. Epidemiology of Gynecologic Cancers, in Principles and Practice of Gynecologic Oncology, 4th Edition W.J. Hoskins, et al., Editors. 2005, Lippincott Williams & Wilkins: Philadelphia. p. 3-9. |
|
Katanoda, K. and D. Qiu, International Comparisons of Cumulative Risk of Uterine Cancer, from Cancer Incidence in Five Continents Vol. VIII. Japanese Journal of Clinical Oncology, 2006. 36(7): p. 474-475 |
|
Gusberg, S.B. and R.E. Hall, Precursors of corpus cancer. III. The appearance of cancer of the endometrium in estrogenically conditioned patients. Obstetrics and Gynecology, 1961. 17: p. 397-412. |
|
Whitehead, M.I. and D. Fraser, Controversies concerning the safety of estrogen replacement therapy. American Journal of Obstetrics and Gynecology, 1987. 156(5): p. 1313-1322. |
|
Antunes, C.M., P.D. Strolley, and N.B. Rosenshein, Endometrial cancer and estrogen use: Report of a large case control study. New England Journal of Medicine, 1979. 300(1): p. 9-13. |
|
Gray, L.A., Sr., W.M. Christopherson, and R.N. Hoover, Estrogens and endometrial carcinoma. Obstetrics and Gynecology, 1977. 49(4): p. 385-389. |
|
Jelovsek, F.R., et al., Risk of exogenous estrogen therapy and endometrial cancer. American Journal of Obstetrics and Gynecology 1980. 137(1): p. 85-91. |
|
Jick, H., et al., Replacement estrogens and endometrial cancer. New England Journal of Medicine, 1979. 300(5): p. 218-222. |
|
Mack, T.M., et al., Estrogens and endometrial cancer in a retirement community. New England Journal of Medicine, 1976. 294(23): p. 1262-1267. |
|
McDonald, T.W., et al., Exogenous estrogen and endometrial carcinoma: case-control and incidence study. American Journal of Obstetrics and Gynecology, 1977. 127(6): p. 572-580. |
|
Shapiro, S., et al., Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium. New England Journal of Medicine, 1980. 303(9): p. 485-489. |
|
Smith, D.C., et al., Association of exogenous estrogen and endometrial carcinoma. New England Journal of Medicine, 1975. 293(23): p. 1164-1167 |
|
Ziel, H.K. and W.D. Finkle, Increased risk of endomtrial carcinoma among users of conjugated estrogens. New England Journal of Medicine, 1975. 293(23): p. 1167-1170. |
|
Grady, D., et al., Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstetrics and Gynecology, 1995. 85(2): p. 304-313. |
|
Peterson, H.B., N.C. Lee, and G.L. Rubin, Genital neoplasia, in Menopause: Physiology and Pharmacology, D.R. Mishell, Jr., Editor. 1986, Year Book Medical Publishers: Chicago. p. 226. |
|
Ewertz, M., G. Schou, and J.D. Boice, Jr., The joint effect of risk factors on endometrial cancer. European Journal of Cancer and Clinical Oncology, 1988. 23(2): p. 189-194. |
|
Hulka, B.S., Replacement estrogens and risk of gynecologic cancers and breast cancer. Cancer, 1987. 60(8 Suppl): p. 1960-1964. |
|
Hulka, B.S., et al., Estrogen and endometrial cancer: cases and two control groups from North Carolina. American Journal of Obstetrics and Gynecology, 1980. 137(1): p. 92-101. |
|
Shapiro, S., et al., Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. New England Journal of Medicine, 1985. 313(16): p. 969-972. |
|
Weiderpass, E., et al., Risk of endometrial cancer following estrogen replacement with and without progestins. Journal of the National Cancer Institute, 1999. 91(13): p. 1131-1137. |
|
Herrinton, L.J. and N.S. Weiss, Postmenopausal unopposed estrogens. Characteristics of use in relation to the risk of endometrial carcinoma. Annals of Epidemiology, 1993. 3(3): p. 308-318. |
|
Robboy, S.J. and R. Bradley, Changing trends and prognostic features in endometrial cancer associated with exogenous estrogen therapy. Obstetrics and Gynecology, 1979. 54(3): p. 269-277. |
|
Silverberg, S.G., et al., Endometrial carcinoma: clinical-pathologic comparison of cases in postmenopausal women receiving and not receiving exogenous estrogens. Cancer, 1980. 45(12): p. 3018-3026. |
|
Killackey, M.A., T.B. Hakes, and V.K. Pierce, Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treatment Reports, 1985. 69(2): p. 237-238. |
|
Early Breast Cancer Trialists' Collaborative Group, Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet, 1998. 351(9114): p. 1451-1467. |
|
Fisher, B., et al., Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. Journal of the National Cancer Institute, 1994. 86(7): p. 527-537. |
|
Mignotte, H., et al., Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case-control study. Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC). International Journal of Cancer, 1998. 76(3): p. 325-330. |
|
Bland, A.E., et al., Relationship between tamoxifen use and high risk endometrial cancer histologic types. Gynecologic Oncology, 2009. 112(1): p. 150-154. |
|
Bergman, L., et al., Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet, 2000. 356(9233): p. 881-887. |
|
Magriples, U., et al., High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. Journal of Clinical Oncology, 1993. 11(3): p. 485-490. |
|
Barakat, R.R., et al., Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecologic Oncology, 1994. 55(2): p. 164-168. |
|
Van Leeuwen, F.E., et al., Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet, 1994. 343(8895): p. 448-452. |
|
American College of Obstetricians and Gynecologists Committee on Gynecologic Practice, ACOG committee opinion no. 336: tamoxifen and uterine cancer. Obstetrics and Gynecology, 2006. 107(6): p. 1475-1478. |
|
Siiteri, P.K., Extraglandular oestrogen formation and serum binding of oestradiol: relationship to cancer. Journal of Endocrinology, 1981. 89(Supplement): p. 119P-129P. |
|
Hershcopf, R.J. and H.L. Bradlow, Obesity, diet, endogenous estrogens, and the risk of hormone-sensitive cancer. American Journal of Clinical Nutrition, 1987. 45(1 Supplement): p. 283-289. |
|
Wynder, E.L., G.C. Escher, and N. Mantel, An epidemiological investigation of cancer of the endometrium. Cancer, 1966. 19(4): p. 489-520. |
|
Swanson, C.A., et al., Relation of endometrial cancer risk to past and contemporary body size and body fat distribution. Cancer Epidemiology Biomarkers and Prevention, 1993. 2(4): p. 321-327. |
|
Henderson, B.E., et al., The epidemiology of endometrial cancer in young women. British Journal of Cancer, 1983. 47(6): p. 749-756. |
|
Lu, L., et al., Long-term overweight and weight gain in early adulthood in association with risk of endometrial cancer. International Journal of Cancer, 2011. 129(5): p. 1237-1243. |
|
Brinton, L.A., et al., Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. American Journal of Obstetrics and Gynecology, 1992. 167(5): p. 1317-1325. |
|
Renehan, A.G., et al., Body-mass index and incidence of cancer: a systematic reivew and meta-analysis of prospective observational studies. Lancet, 2008. 371(9612): p. 569-578. |
|
Weiderpass, E., et al., Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer. Cancer Causes and Control, 2000. 11(2): p. 185-192. |
|
Mauland, K.K., et al., High BMI is significantly associated with positive progesterone receptor status and clinico-pathological markers for non-aggressive disease in endometrial cancer. British Journal of Cancer, 2011. 104(6): p. 921-926. |
|
Calle, E.E., et al., Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. New England Journal of Medicine, 2003. 348(17): p. 1625-1638. |
|
Von Gruenigen, V.E., et al., Treatment effects, disease recurrence, and survival in obese women with early endometrial carcinoma: a Gynecologic Oncology Group study. Cancer, 2006. 107(12): p. 2786-2791. |
|
Bevier, M., J. Sundquist, and K. Hemminki, Does the time interval between first and last birth influence the risk of endometrial and ovarian cancer? European Journal of Cancer, 2011. 47(4): p. 586-591. |
|
Parazzini, F., et al., Reproductive factors and risk of endometrial cancer. American Journal of Obstetrics and Gynecology, 1991. 164(2): p. 522-527. |
|
Kessler, I.I., Cancer and diabetes mellitus. A review of the literature. Journal of Chronic Disease, 1971. 23(8): p. 579-600. |
|
Parazzini, F., et al., Diabetes and endometrial cancer: an Italian case-control study. International Journal of Cancer, 1999. 81(4): p. 539-542. |
|
Elwood, J.M., et al., Epidemiology of endometrial cancer. Journal of the National Cancer Institute, 1977. 59(4): p. 1055-1060. |
|
Anderson, K.E., et al., Diabetes and endometrial cancer in the Iowa women's health study. Cancer Epidemiology Biomarkers and Prevention, 2001. 10(6): p. 611-616. |
|
Shoff, S.M. and P.A. Newcomb, Diabetes, body size, and risk of endometrial cancer. American Journal of Epidemiology, 1998. 148(3): p. 234-240 |
|
Burzawa, J.K., et al., Prospective evaluation of insulin resistance among endometrial cancer patients. American Journal of Obstetrics and Gynecology, 2011. 204(4): p. 355.e1-355.e7. |
|
Soliman, P.T., et al., Association between adiponectin, insulin resistance, and endometrial cancer. Cancer, 2006. 106(11): p. 2376-2381. |
|
Berstein, L.M., et al., Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. Journal of Cancer Research and Clinical Oncology, 2004. 130(11): p. 687-693. |
|
Zucchetto, A., et al., Hormone-related factors and gynecological conditions in relation to endometrial cancer risk. European Journal of Cancer Prevention, 2009. 18(4): p. 316-321. |
|
Way, S., The aetiology of carcinoma of the body of the uterus. Journal of Obstetrics and Gynecology of the British Empire, 1954. 61(1): p. 46-58. |
|
MacMahon, B., Risk factors for endometrial cancer. Gynecologic Oncology, 1974. 2(2-3): p. 122-129. |
|
McPherson, C.P., et al., Reproductive factors and risk of endometrial cacner. The Iowa Women's Health Study. American Journal of Epidemiology, 1996. 143(12): p. 1195-1202. |
|
Schroeder, R., Granulosa cell tumors of the ovaries with glandular cystic hyperplasia of the endometrium and beginning carcinoma on this basis. Zentralblatt Gynakologie, 1922(1): p. 195. |
|
Diddle, A.W., Granulosa- and theca-cell ovarian tumors: prognosis. Cancer, 1952. 5(2): p. 215-228. |
|
Larson, J.A., Estrogens and endometrial carcinoma. Obstetrics and Gynecology, 1954. 3(5): p. 551-572. |
|
Dockerty, M.B. and R.L. Jackson, The Stein-Leventhal syndrome: analysis of 43 cases with special reference to association with endometrial carcinoma. American Journal of Obstetrics and Gynecology, 1957. 73(1): p. 161-173. |
|
Chamlian, D.L. and H.B. Taylor, Endometrial hyperplasia in young women. Obstetrics and Gynecology, 1970. 36(5): p. 659-666. |
|
Fearnley, E.J., et al., Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study. Cancer Causes and Control, 2010. 21(12): p. 2303-2308. |
|
Gruber, S.B. and W.D. Thompson, A population-based study of endometrial cancer and familial risk in younger women. Cancer and hormone study group. Cancer Epidemiology Biomarkers and Prevention, 1996. 5(6): p. 411-417. |
|
Meyer, L.A., R.R. Broaddus, and K.H. Lu, Endometrial cancer and Lynch syndrome:clinical and pathologic considerations. Cancer Control, 2009. 16(1): p. 14-22. |
|
Boks, D.E., et al., Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. International Journal of Cancer, 2002. 102(2): p. 198-200. |
|
Lu, K.H., et al., Gynecologic cancer as a "sentinel cancer" for women with herditary nonpolyposis colorectal cancer syndrome. Obstetrics and Gynecology, 2005. 105(3): p. 569-574. |
|
Lancaster, J.M., et al., Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecologic Oncology, 2007. 107(2): p. 159-162. |
|
Lindor, N.M., et al., Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. Journal of the American Medical Association, 2006. 296(12): p. 1507-1517. |
|
Schmeler, K.M., et al., Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. New England Journal of Medicine, 2006. 354(3): p. 261-269 |
|
Levi, F., C. La Vecchia, and A. Decarli, Cigarette smoking and the risk of endometrial cancer. European Journal of Cancer and Clinical Oncology, 1987. 23(7): p. 1025-1029 |
|
MacMahon, B., et al., Cigarette smoking and urinary estrogens. New England Journal of Medicine, 1982. 307(17): p. 1062-1065. |
|
Baron, J.A., Smoking and estrogen-related disease. American Journal of Epidemiology, 1984. 119(1): p. 9-22 |
|
Franks, A.L., J.S. Kendrick, and C.W. Tyler, Jr., Postmenopausal smoking, estrogen replacement, and the risk of endometrial cancer. American Journal of Obstetrics and Gynecology, 1987. 156(1): p. 20-23. |
|
Lesko, S.M., et al., Cigarette smoking and the risk of endometrial cancer. New England Journal of Medicine, 1985. 313(10): p. 593-596. |
|
Yang, H.P., et al., Active and passive cigarette smoking and the risk of endometrial cancer in Poland. European Journal of Cancer, 2010. 46(4): p. 690-696. |
|
Pike, M.C., Age-related factors in cancers of the breast, ovary, and endometrium. Journal of Chronic Disease, 1987. 40(Supplement 2): p. 59S-69S. |
|
Weiss, N.S. and T.A. Sayvetz, Incidence of endometrial cancer in relation to the use of oral contraceptives. New England Journal of Medicine, 1980. 302(10): p. 551-554. |
|
Kaufman, D.W., et al., Decreased risk of endometrial cancer among oral-contraceptive users. New England Journal of Medicine, 1980. 303(18): p. 1045-1047. |
|
Weiderpass, E., et al., Use of oral contraceptives and endometrial cancer risk (Sweden). Cancer Causes and Control, 1999. 10(4): p. 277-284. |
|
Beining, R.M., et al., Meta-analysis of intrauterine device use and risk of endometrial cancer. Annals of Epidemiology, 2008. 18(6): p. 492-499. |
|
Benshushan, A., et al., IUD use and the risk of endometrial cancer. European Journal of Obstetrics and Gynecology and Reproductive Biology, 2002. 105(2): p. 166-169. |
|
MacMahon B: Risk factors for endometrial cancer. Gynecol Oncol 122: 2, 1974 |
|
Wynder EL, Escher GC, Mantel N: An epidemiological investigation of cancer of the endometrium. Cancer 19: 489, 1966 |
|
Masubichi K, Nemoto H: Epidemiologic studies on uterine cancer at Cancer Institute Hospital, Tokyo, Japan. Cancer 30: 268, 1972 |
|
Elwood JM, Cole P, Rothman K et al: Epidemiology of endometrial cancer. J Natl Cancer Inst 59: 1055, 1977 |
|
Way S: The aetiology of carcinoma of the body of the uterus. J Obstet Gynaecol Br Emp 61: 46, 1954 |
|
Kessler II: Cancer and diabetes mellitus: A review of the literature. J Chronic Dis 23: 579, 1971 |
|
Lucas WE, Yen SSC: A study of endocrine and metabolic variables in postmenopausal women with endometrial carcinoma. Am J Obstet Gynecol 134: 180, 1979 |
|
Lucas WE: Causal relationships between endocrine-metabolic variables in patients with endometrial carcinoma. Obstet Gynecol Surv 29: 507, 1974 |
|
Jackson RL, Dockerty MB: The Stein-Leventhal syndrome: Analysis of 43 cases with special reference to association with endometrial carcinoma. Am J Obstet Gynecol 73: 161, 1957 |
|
Chamlian DL, Taylor HB: Endometrial hyperplasia in young women. Obstet Gynecol 36: 659, 1970 |
|
Schottenfeld D, Berg J: Incidence of multiple primary cancers: IV. Cancers of the female breast and genital organs. J Natl Cancer Inst 46: 161, 1971 |
|
Frick HC II, Munnell EW, Richart RM et al: Carcinoma of the endometrium. Am J Obstet Gynecol 115: 663, 1973 |
|
Lynch HT, Drush AJ, Larsen AL: Heredity and endometrial carcinoma. South Med J 60: 231, 1967 |
|
Wagoner J, Connelly RR, cited by MacMahon B: Risk factors for endometrial cancer. Gynecol Oncol 122: 2, 1974 |
|
Schroeder R: Granulosa cell tumors of the ovaries with glandular cystic hyperplasia of the endometrium and beginning carcinoma on this basis. Zentralbl Gynaekol 1: 195, 1922 |
|
Diddle AW: Granulosa and theca cell ovarian tumors: Prognosis. Cancer 5: 215, 1952 |
|
Larson JA: Estrogens and endometrial cancer. Obstet Gynecol 3: 551, 1954 |
|
Greene JW: Feminizing mesenchymomas with associated endometrial cancer. Am J Obstet Gynecol 74: 31, 1957 |
|
Cullen TS: Cancer of the Uterus. New York, Appleton-Century-Crofts, 1900 |
|
Gusberg SB: Precursors of corpus carcinoma: Estrogens and adenomatous hyperplasia. Am J Obstet Gynecol 54: 905, 1947 |
|
Gusberg SB, Kaplan AL: Precursors of corpus cancer: IV. Adenomatous hyperplasia and stage O carcinoma of the endometrium. Am J Obstet Gynecol 87: 662, 1963 |
|
MacDonald PC, Edmon CD, Hemsall DL et al: Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endometrial cancer. Am J Obstet Gynecol 130: 448, 1978 |
|
Nisker JA, Hammond GL, Davidson BJ et al: Serum sex hormone-binding globulin capacity and the percentage of free estradiol in postmenopausal women with and without endometrial carcinoma. Am J Obstet Gynecol 138:637 |
|
Hulka BS: Replacement estrogen and risk of gynecologic and breast cancer. Cancer 60: 1960, 1987 |
|
Ewertz M, Schon G, Bioce JD Jr: The joint effect of risk factors on endometrial cancer. Eur J Cancer Clin Oncol 24: 189, 1988 |
|
Whitehead M, Fraser D: Controversies concerning the safety of estrogen replacement therapy. Am J Obstet Gynecol 156: 1313, 1987 |
|
Peterson HB, Lee NC, Rubin GL: Genital neoplasia. In Mishell D (ed): Menopause: Physiology and Pharmacology, pp 275. Chicago, Year Book Medical Publishers, 1986 |
|
Siiteri PK: Extraglandular oestrogen formation and serum binding of oestradiol: Relationship to cancer. J Endocrinol 89: 119, 1981 |
|
Hershcopf RJ, Bradlow HL: Obesity, diet, endogenous estrogens, and the risk of hormone-sensitive cancer. Am J Clin Nutr 45: 283, 1987 |
|
Jeffrey JD, Taylor R, Robertson D, Stuart GCE: Endometrial carcinoma occurring in patients under the age of 45 years. Am J Obstet Gynecol 156: 366, 1987 |
|
Key TJA, Pike MC: The Dose-effect relationship between “unopposed” oestrogens and endometrial mitotic rate: Its central role in explaining and predicting endometrial cancer risk. Br J Cancer 57 (2): 205, 1988 |
|
Henderson BE, Casagrande JT, Pike MC, et al: The epidemiology of endometrial cancer in young women. Br J Cancer 47: 749, 1983 |
|
Pike MC: Age related factors in cancers of the breast, ovary and endometrium. J Chronic Dis (Suppl 2)40:59S, 1987 |
|
Whitehead MI: The effects of oestrogens and progestogens on the postmenopausal endometrium. Maturitas 1: 87, 1978 |
|
Studd JWW, Thom MH: Oestrogens and endometrial hyperplasia. In Studd JWW (ed): Progress in Obstetrics and Gynecology, Vol 1, pp 182. Edinburgh, Churchhill Livingstone, 1981 |
|
Whitehead MI, Townsend PT, Pryse-Davies J et al: Effects of various types and dosages of progestogens on the postmenopausal endometrium. J Reprod Med 27: 539, 1982 |
|
Magos AL, Brincat M, Studd JWW et al: Amenorrhea and endometrial atrophy with continuous oral estrogen and progestogen therapy in postmenopausal women. Obstet Gynecol 65: 496, 1985 |
|
Levi F, Vecchia CL, De Carli A: Cigarette smoking and the risk of endometrial cancer. Eur J Cancer Clin Oncol 23 (7): 1025, 1987 |
|
MacMahon B, Trichopoulos D, Cole P, Brown J: Cigarette smoking and urinary estrogens. N Engl J Med 307: 1062, 1982 |
|
Baron JA: Smoking and estrogen-related disease. Am J Epidemiol 119: 9, 1984 |
|
Frands AI, Kendrick JS, Tyler CW Jr: Postmenopausal smoking, estrogen replacement therapy, and the risk of endometrial cancer. Am J Obstet Gynecol 156: 20, 1987 |
|
Lesko SM, Rosenberg L, Kaufman DW et al: Cigarette smoking and the risk of endometrial cancer. N Engl J Med 313: 593, 1985 |
|
Michnovicz JJ, Herschkopf RJ, Naganuma H et al: Increased 2-hydroxylation of estradiol and possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 315: 1305, 1986 |
|
Adami H, Krusema UB, Bergkvist L et al: On the age-dependent association between cancer of the breast and of the endometrium. A nationwide cohort study. Br J Cancer 55 (1): 77, 1987 |
|
Anderson KE, Kappos A, Conney AH et al: The influence of dietary protein and carbohydrate on the principal oxidative biotransformation of estradiol in normal subjects. J Clin Endocrinol Metab 59: 103, 1984 |
|
Hulka BS, Fowler WC, Kaufman DG et al: Estrogen and endometrial cancer: Cases and two control groups from North Carolina. Am J Obstet Gynecol 137: 92, 1980 |
|
Austin DF, Roe KM: The decreasing risk of endometrial cancer: Public health implications. Am J Public Health 72: 65, 1982 |
|
Kennedy DL, Baum C, Forbes MD: Noncontraceptive estrogen and progestins: Use patterns over time. Obstet Gynecol 65: 441, 1985 |
|
Shapiro S, Kelly JP, Roseberg L et al: Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 313: 969, 1985 |
|
Kohorn EI: The present state of endometrial carcinoma: Controversies and problems. Conn Med 51: 495, 1987 |
|
Deligdisch L, Holinka CF: Endometrial carcinoma: Two diseases? Cancer Detect Prev 10: 237, 1987 |
|
Smith EM, Anderson B: Symptomatology, delay, and stage of disease in endometrial cancer. Cancer Detect Prev 10: 247, 1987 |
|
Toppozada MK, Ismail AAA, Hamid RSM et al: Progesterone challenge test and estrogen assays in menopausal women with endometrial adenomatous hyperplasia. Int J Gynaecol Obstet 26: 115, 1988 |
|
Gambrell RD Jr: Use of progestogen therapy. Am J Obstet Gynecol 156: 1304, 1987 |