Abstract

Uterine Cancer (UC) is the most common cancer in women in the United States. Both new cases and death increase yearly. In a normal uterus, the endometrium, or lining, thickens every month unless the woman is pregnant or postmenopausal. If an egg is not fertilized, the lining is shed in the form of menstruation. Progesterone and estrogen are produced in and released from the ovaries. Their release is triggered by the hypothalamus. The corpus luteum, a temporary gland in the ovary, releases progesterone that causes the endometrium to thicken as the egg moves through the fallopian tube towards the uterus. If the egg is not fertilized, the corpus luteum ceases to exist. Like other cancers, UC occurs when cells grow abnormally. The precise cause of UC is still unknown but various theories are presented. While various treatments exist, UC is often not diagnosed until a woman has symptoms and by then, the cancer may have metastasized. Unlike annual PAP smears that detect cervical cancer, no such routine test has been implemented. A current clinical trial may introduce a simple yet revolutionary method for women to collect intravaginal DNA at home to send to a laboratory for testing and early detection.

Uterine Cancer

Uterine cancer (UC), the most common gynecologic cancer, killed 10,733 women in the United States in 2016. The rate of new cases of UC for that year was 56,808. The age group with the most new cases (10,260 women) were between the ages of 65-69, though there were 61 women between the ages of 20-24 who also were diagnosed with UC that year. Of the new cases, 27.6% were White, 27% were Black, 24.6% were Hispanic, 19.4% were Asian or Pacific Islander, and 16.9% were American Indian or Alaskan Native (Centers for Disease Control and Prevention [CDC], 2019). But according to a recent study, Black women had the worst five-year survival rate (54%) of any ethnic group (Baskovic, Lichtensztajn, Nguyen, Karam, & English, 2018). Despite technological advances in medicine, new incidents of UC increased 0.7% each year from 1999 to 2015 and death rates also increased, at a rate of 1.1% each year from 1999 to 2016 (Henley, Miller, Dowling, Benard, & Richardson, 2018).

Normal Structure and Function of the Uterus

The uterus consists of three layers: the exterior layer is the serosa, the middle layer is the myometrium, and the interior layer is the endometrium. The endometrium has three layers: a basal layer, an intermediate spongiosa layer, and an epithelial cell layer. The top of the uterus is the fundus, the middle of the uterus is the body, or corpus, and the bottom of the uterus is the cervix. The function of the uterus is to house and protect the fertilized egg as it develops into an embryo and fetus. During childbirth, the uterus contracts to allow the baby to be born (Canadian Cancer Society, 2019).

There are two female reproductive cycles: the ovarian cycle and the endometrial cycle. The ovarian cycle begins with the follicular phase when the endometrium is at its thickest. If there isn’t a fertilized egg, there are low levels of the luteinizing hormone (LH) and the follicle-stimulating hormone (FSH) in the anterior pituitary gland and both estrogen and progesterone levels remain low.  and menstruation (shedding of the endometrium) occurs. The hypothalamus releases the gonadotropin-releasing hormone (GnRH) that allows the gonadotropic cells in the anterior pituitary gland to produce FSH followed by an increase of LH after one or two days. Ovarian follicles then produce exponentially more estradiol, which both inhibits the secretion of FSH and to a lesser degree LH, and stimulates their synthesis. Meanwhile, the endometrial cycle begins with the menstrual stage, when the endometrium is thin. The estradiol causes the basal layer of the endometrium to begin to thicken during the proliferative stage of the endometrial cycle


(Knudston & McLaughlin, 2019).

During the ovulation stage of the ovarian cycle, the follicle fills with fluid and hormone-secreting granulosa cells and inhibits FSH further.  The estradiol, as well as GnRH and progesterone, causes LH production to increase. This leads to lowered estradiol levels and higher progesterone levels. The LH stimulates enzymes to open the follicle to release the ovum and begin meiosis (Knudston & McLaughlin, 2019).

During the luteal phase of the ovarian cycle what is left of the follicle becomes the corpus luteum which secretes progesterone. This corresponds to the secretory phase of the endometrial cycle, and the progesterone prepares the endometrium for implantation by increasing glycogen and blood flow to the endometrium. LH and FSH levels drop and if implantation does not occur, the corpus luteum becomes the corpus albicans, estradiol and progesterone levels are lowered causing the spongiosa and epithelial layers to shed in the form of menstrual blood, leading back again to the menstrual phase. If implantation occurs, the corpus luteum does not degenerate but remains functional in early pregnancy, supported by human chorionic gonadotropin (HCG) that is produced by the developing embryo (Knudston & McLaughlin, 2019). Pregnancy tests detect high HCG levels. While the phases do not line up neatly, they overlap and influence each other.

Disease Process

The majority (more than 95%) of UC is endometrial carcinoma, or abnormal cell growth that starts in the endometrium. 75-80% of these cancers form in the endometrium glands, and are known as endometrioid carcinoma, which in turn may or may not include non-cancerous squamous cells. Other kinds of endometrioid carcinoma include villoglandular, secretory, and ciliated


cell (Canadian Cancer Society, 2019). Like other cancers, the exact mechanism that causes women to develop UC is still unknown. There are theories that UC may be caused by a number of factors, including “environmental factors, including estrogen, an


abnormal mismatch repair (MMR) system, genetic abnormalities, and aberrant methylation of DNA and microRNA” (Banno, Yanokura, Iida, Masuda, & Aoki, 2014, p. 1957).

The Estrogen Effect

If a woman produces too much estrogen and too little progesterone, she may develop atypical endometrial hyperplasia, or thickening of the endometrium, which may in turn make her more susceptible to endometrial carcinoma (Type I). But if a woman has already passed menopause (and no longer producing estrogen), the carcinoma may develop in a typical endometrium. Known as Type II Endometrial Cancer, the prognosis is worse in this case because the cells are not as differentiated as in Type I. (Banno et al., 2014)

Abnormal Mismatch Repair System

Errors may occur during DNA replication and an abnormal mismatch repair (MMR) system repairs these errors. Lynch syndrome is a hereditary cancer disorder which causes mutations in MMR genes. According to Zakhour et al. (2017), 2-5% of endometrial cancers are attributed to Lynch syndrome. They found that Lynch syndrome was associated with at least 50% of the young women they sampled with endometrial cancer. Unfortunately, they also found that these women were not screened for Lynch syndrome because their family histories did not meet the Amsterdam II criteria for testing (Zakhour et al., 2017), suggesting that screening criteria may need to be expanded so that women may be able to be diagnosed and treated sooner.

Aberrant DNA methylation

Normal DNA methylation (Tao & Freudenheim, 2010) occurs when methyl group bonds to cytosine residues with the help of DNA cytosine methyltranseferase enzymes to form methylcytosine, which is helpful in transcription, normal development, silencing some genes, and gene imprinting. Aberrant DNA methylation occurs when tumor suppressing genes are silenced, allowing tumors to grow. Tao and Freudenheim (2010) found that aberrant DNA methylation was present before diagnosis, suggesting that DNA methylation should be investigated to detect endometrial cancer early.

PTEN Mutations

One of the tumor suppressor genes, the phosphatase and tensin homolog gene (PTEN), is responsible for “the inhibition of cell migration and spreading and focal adhesion” (Tao & Freudenheim, 2010, p. 493). In other words, PTEN normally both stops cancer cells from attaching to healthy cells and stops the cancer cells from metastasizing. 26-80% of endometrial cancers are associated with PTEN mutations


(Tao & Freudenheim, 2010). This suggests that screening for PTEN may be informative in assessing risk for EC.

Tomaxifen

Segev et al. (2013) found that women who were given tamoxifen (for breast cancer) were four times more likely to develop UC after they reached menopause. Tamoxifen is a “selective estrogen receptor modulator” which is used both to prevent and treat breast cancer as it is antiestrogenic, meaning it blocks estrogen, in mammary (breast) linings by binding with the estrogen receptors. But tamoxifen is proestrogenic on the uterine lining; in other words, it acts like estrogen in the endometrium thus increasing the likelihood of endometrial cancer due to hyperplasia (Sporn & Lippman, 2003).

BRCA1/2

While women who are found to be carriers of mutations in the BRCA1 and BRCA2 genes are seven to twenty times more likely to develop breast and ovarian cancer than those who are not carriers, recent research has indicated that this genetic screening may also be valuable in terms of UC. Laitman et al. (2019) explored the rates of the UC in Jewish women in Israel who are carriers of the BRCA1/2 mutations with expected and actual rates of UC in non-carrier women. They found that BRCA1/2 carriers were 3.98 times more likely to develop UC compared to the general Jewish population. Regardless of type of UC and whether or not the woman also developed breast cancer, the increased risk remained significant. Current recommendations for BRCA1/2 carriers include undergoing risk reducing salpingo-oophorectomy (RRSO), or the removal of the ovaries and fallopian tubes. The authors suggest that given the significant risk increase for UC, undergoing a hysterectomy (removal of the uterus) may be considered. The study did not, however, take into account whether or not women received tomaxifen as that data was not available.

Obesity

Women with a high (over 30 kg/m²) Body Mass Index (BMI), are two times more likely to develop UC than women with a healthy BMI (Nunez, Bauman, Egger, Sitas, & Nair-Shalliker, 2017, 61). Adipose (fat) tissue contain the aromatese enzyme converts androgen into estrogen. Thus, women who are obese may have more estrogen than other women which may lead to hyperplasia and UC. According to Lee et al. (2018), “adiposity has been associated with other factors that may drive tumorigenesis in general, including increased inflammation, depressed immune function, and chronic insulin resistance and hyperinsulinemia.”  The insulin in turn, can both stimulate cell growth and act as an anti-apoptotic, protecting cells from cell death (Nunez, Bauman, Egger, Sitas, & Nair-Shalliker, 2017, 61). The use of Metformin for diabetic patients has shown promising results in decreasing the incidence of UC by causing apoptosis (cell death) and “inhibiting cell migration” (Lee et al., 2018).

Modifiers

Diet

Folate includes a methyl group that can be used for methylation and one carbon metabolism (the transfer of one-carbon groups), while methionine, vitamins B2, B6, and B12 are important for one carbon metabolism (Tao & Freudenheim, 2010). High levels of folate are found in dark green leafy vegetables, liver, legumes, asparagus, and avocado. Methionine is in meat, fish, and dairy. Vitamin B2, or riboflavin, is found in eggs, green vegetables, and grains. Chicken, fish, potatoes, and fruit are all sources of vitamin B6. Vitamin 12 is present in fish, chicken, eggs, dairy, beef liver, and clams (National Institutes of Health, 2019).

Soy and soy products, which contain phytoestrogens like genistein, may also help reduce endometrial cancer. The hypothesized mechanism of action involved is DNA methylation but more research is needed to examine the appropriate amount of soy needed to help reduce the risk (Tao & Freudenheim, 2010).

Hormone treatments

A combination of progesterone and estrogen may be given as hormone therapy or as oral contraceptive to reduce the risk of Type I EC. (Tao 2017) The rationale is that too much estrogen and not enough progesterone may cause the hyperplasia in Type I EC but if a woman is given an appropriate combination of the hormones, the thickening may not occur and therefore the risk of cancer is lowered (Tao & Freudenheim, 2010).

Lifestyle

Regular exercise may serve as a protective factor against UC. Women who engaged in high levels of physical activity (vigorous activity at least once a day) were 53% less likely to develop UC than women who did not engage in any physical activity (Nunez, Bauman, Egger, Sitas, & Nair-Shalliker, 2017, 61), suggesting that regular vigorous exercise may serve as a protective factor for women.

Pregnancy

Women who have been pregnant have reduced risk of developing EC and the risk is reduced as she has more children up to five or more. During pregnancy, a woman produces less estrogen and more progesterone. In addition, when a woman is pregnant, she does not menstruate, so her estrogen levels do not increase, and she has less estrogen buildup in her body. Pocobelli et al. (2011) found that women who gave birth for the first time after age 35 had decreased risk for EC. They hypothesize that this may be due to the fact that progesterone increases during pregnancy, which suppresses the estrogen production.

Breastfeeding

When a woman breastfeeds, her estrogen production is suppressed. Thus, her risk of developing EC may be reduced as well. In fact, Jordan et al. (2017) found that women who reported having ever breastfed had a 11% risk reduction for EC compared to women who did not ever breastfeed. In addition, they found that the risk reduction increased as a woman breastfed her baby for longer up to 6-9 months.

Bariatric Surgery

Roux-en-Y is the most common type of gastric bypass, which is the most common method of bariatric, or weight-loss surgery. In this procedure, the surgeon cuts off a small pouch of the woman’s stomach from the rest and attaches the middle of her small intestine to the small pouch. This prevents the woman from eating too much food or absorbing too many nutrients. Bariatric surgery may be an option for women who are extremely obese (BMI over 40) or are moderately obese (BMI 35-39.9) and have serious health problems related to their weight. Women who undergo bariatric surgery must be screened to qualify and may have to commit to adopting a healthier lifestyle and follow-up monitoring after surgery (Mayo Clinic, 2019).

According to a recent study, obese women who have had bariatric surgery were 71% less likely than obese women who did not have bariatric surgery to develop UC. When these women were able to maintain normal weight after bariatric surgery, their risk of developing UC was further reduced to 81% (Ward et al., 2014). Unfortunately, the study did not specify what types of bariatric surgery had been performed and this may have been a significant factor.

Detection

While women undergo routine annual pap smears which screens for cervical cancer, there is no comparable screening process for UC. Instead, women who have a family history of UC or another lynch syndrome cancer such as colon or ovarian cancer, may request genetic testing and regular check-ups. The most common symptom of UC is bleeding in post-menopausal women. Doctors may diagnose UC by doing a biopsy or ultrasound. Bakkum-Gamez et al (2015) investigated the use of tampons to detect EC. She found that tampons collected sufficient fluid compared to a Tao brush, which is usually used to collect samples from the endometrium. A woman would be able to insert the tampon at home to collect a sample of DNA from her endometrium, and then send it to a lab for testing. This would be especially helpful for early detection, repeated testing, and testing for women in inaccessible locations. Dr. Nicolas Wentzensen of the National Cancer Institute recently began a clinical trial (clinicaltrials.gov, NCT 03538665) testing the tampon hypothesis by having women aged 45 or older insert tampons for a half hour before undergoing a hysterectomy. The experimental group must have diagnosed EC or EC precursors, while the control group must have benign conditions such as fibroids or polyps.

Treatments

Depending on the type and stage of the cancer, treatments may include surgery, radiation, hormone therapy, or chemotherapy. Surgery involves a hysterectomy and possibly the removal of the fallopian tubes and ovaries as well. Lymph nodes removed during surgery may be examined to indicate the stage of cancer to better inform treatment (Mayo Clinic, 2019b).

Radiation therapy involves powerful energy beams directed at specific parts of the body either externally or internally through the vagina. Radiation therapy may be indicated before, after, or in place of surgery. Radiation may be used before surgery to reduce the size of the tumor by damaging the cancer DNA or after surgery to reduce the chances of recurrence. Women who are not healthy enough to have surgery may only have radiation therapy (Mayo Clinic, 2019b).

Hormone therapy involves taking medications to lower hormones such as estrogen that may be facilitating tumor growth in the uterus and beyond. Oral or intravenous chemotherapy may be indicated to kill cancer cells using chemicals. Like radiation therapy, it may be used before or after surgery. Targeted drug therapy may also be used with chemotherapy to weaken cancer cells. Immunotherapy assists the woman’s immune system to attack the cancer cells. In addition, palliative care is recommended to help with pain relief and managing symptoms of the disease as well as side-effects of the treatments


(Mayo Clinic, 2019b).

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