This chapter should be cited as follows: This chapter was last updated:
Holman, L, Lu, K, Glob. libr. women's med.,
(ISSN: 1756-2228) 2012; DOI 10.3843/GLOWM.10236
January 2012

Endometrial carcinoma and sarcoma

The Epidemiology of Endometrial Cancer

Laura L. Holman, MD
Fellow, Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, Texas, USA
Karen H. Lu, MD
Professor, Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, Texas, USA

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.1 As 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


Risk assessment
helpful


Risk assessment
recommended

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. 

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