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Endometrial cancer, also known as uterine cancer, most commonly occurs in older women. Fortunately, it is usually caught in its early stages when it is highly curable. Endometrial cancer involves abnormal cellular growth of the endometrium, the tissue that lines a woman’s uterus and is normally shed each month during menstruation. Although accounting for only 6% of all cancers among women, it is the fourth most common cancer after breast, colorectal, and lung cancers.


Endometrial cancer is predominantly a disease of postmenopausal women: 95% of cases occur in women 40 years of age or older. Surgical removal of the uterus (hysterectomy), often combined with radiation, usually cures endometrial cancer. Chemotherapy is used in advanced cases.
Figure 1. Female reproductive anatomy
Causes

Endometrial cancer can result from excess amounts of the female hormone estrogen. Excess, or “unopposed” estrogen can result from a number of causes. Endometrial cancer can develop over time when estrogen is not counterbalanced by sufficient progesterone, another female hormone. This situation is referred to as “unopposed” estrogen.


The cancerous cells grow from glandular cells in the lining of the uterus, and are called adenocarcinomas. Most endometrial cancers are of this “endometrioid” type, otherwise called “type I” endometrial cancer, and tend to arise when there is unopposed estrogen.


Obesity is associated with excess estrogen. This is because the hormones that can become estrogen in the body are converted to active estrogen in the body fat. Therefore, the more body fat, the higher the estrogen levels in the bloodstream and the greater the chance of getting endometrial cancer.


In addition, women with polycystic ovarian syndrome can develop type I endometrial cancers. Polycystic ovary syndrome is a condition that results in very irregular periods and many cycles during which patients do not successfully ovulate.


Another uncommon cause of unopposed estrogen is estrogen-secreting tumors, such as ovarian tumors.
There is another type of endometrial cancer that is not associated with excess or unopposed estrogen. Cancer of other cell types of the endometrium also occur, such as “serous” carcinomas, called “type II” endometrial cancer.



This type of cancer tends to have a poorer prognosis than type I adenocarcinomas, and behaves like most ovarian cancers.
Endometrial cancer tends to spread first by invading the muscular wall of the uterus, and then the other pelvic organs before spreading through lymph vessels to lymph nodes. The tumor may invade deep into the muscular wall of the uterus, as well as into surrounding structures such as the vagina, bladder, or rectum. Cancerous cells can also break off from the tumor and travel (metastasize) into the vagina or through the blood or lymphatic systems to the lymph nodes, lungs, liver, bones, or brain.
Symptoms

Abnormal bleeding occurs in 98% of cases of endometrial cancer. Endometrial cancer almost always causes vaginal bleeding. In women who are definitely postmenopausal, any vaginal bleeding is considered abnormal until proven otherwise. So if you have stopped having your periods and are in menopause, but you experience vaginal bleeding, you should see your doctor promptly.


Women who are taking postmenopausal hormone replacement therapy (HRT) may have vaginal bleeding, depending on the schedule and type of hormones prescribed. If a women is experiencing bleeding on HRT, she should discuss this with her doctor.
Women who are still menstruating may experience:

• bleeding between periods
• overly-frequent periods (less than 21 days apart)
• prolonged, heavy periods

Bleeding may be excessive or may appear as mere spotting or as a blood-tinged discharge. Some women have abnormal vaginal discharge that is not bloody.
Symptoms in advanced cancer may include pelvic pain, a mass in the pelvis, or weight loss.
Risk Factors

Endometrial cancer is mostly a disease of postmenopausal women. Most cases of endometrial cancer in the U.S. happen in women between the ages of 50 and 70 years of age. Fewer than 5% of cases occur in women younger than 40.
Obesity and diabetes are two important risk factors. Studies have shown that the risk of endometrial cancer increases two-to-tenfold in obese women, with the greatest risk for the most overweight women.
Although diabetic women tend to be overweight, diabetes also appears to be an independent risk factor. Women with diabetes who are not overweight also develop endometrial cancer in greater numbers, and heavy women with diabetes are at higher risk than women of the same weight who do not have diabetes.



Figure 2. Body mass index (BMI) calculator
Taking estrogen without the counteracting hormone, progesterone, increases the risk of endometrial cancer. Tamoxifen (Nolvadex), a drug used to treat breast cancer, that acts like estrogen in the uterus, also increases the risk. When estrogen replacement therapy was first offered to women to help alleviate symptoms of menopause and enhance other aspects of health, rates of endometrial cancer increased significantly nationwide. Doctors now realize that progesterone, the female hormone that counteracts the effects of estrogen, must also be given as part of hormone replacement therapy for women who have not had a hysterectomy.


Tamoxifen is classified as an “anti-estrogen” drug, and is used to treat women with breast cancer as well as endometrial cancer in some cases. It does, however, act as a weak estrogen in the endometrium, and carries a 1 in 500 risk of causing endometrial cancer, which is about twice the rate of cancer in women who do not take tamoxifen. Because most of the endometrial cancers that develop as a result of tamoxifen are type I cancers and are stage I (see below), they have an excellent prognosis. Indeed, there is no increase in mortality from endometrial cancer that arises in these women.


Thus, for women who have had breast cancer, the benefits of taking tamoxifen to prevent a recurrence clearly outweigh the relatively lower risk of developing endometrial cancer. Healthy women who have a strong family history of breast cancer also may consider taking tamoxifen, but must more carefully assess the potential risks and benefits.


Women who take tamoxifen must be informed about the symptoms of endometrial cancer, and seek help if abnormal bleeding develops.
All women are naturally exposed to estrogen throughout their lives.


However, some have relatively higher levels and are more at risk. Women who do not ovulate regularly (release an egg at midcycle) are more likely to develop a precancerous condition of the endometrium called endometrial hyperplasia. This condition results from abnormal regulation of the hormones associated with the menstrual cycle, and an excess of circulating estrogen for longer intervals during a woman's menstrual cycle. Women at risk for endometrial hyperplasia include those with polycystic ovarian syndrome, for example.


In addition, women who have more periods during their lives—those who start menstruation at an early age, go through late menopause, or have no children—are more likely to develop endometrial cancer.


Women who do not ovulate because ovulation is suppressed by birth control pills actually have a lower risk of endometrial cancer. Therefore, it is not the lack of ovulation that is the problem; it is the lack of proper regulation of ovulation, which also produces abnormal hormonal levels of estrogen and progesterone during the menstrual cycle.


Women who have had breast cancer, ovarian cancer, or certain colon cancers are at higher risk. Another inherited condition that is associated with a high rate of inherited colon and uterine cancer, called hereditary nonpolyposis colon cancer (Lynch II syndrome), is also associated with a high risk of endometrial cancer.
Diagnosis

Women with postmenopausal or abnormal vaginal bleeding are usually referred to a gynecologist for diagnostic tests.
A woman will undergo an endometrial biopsy (EMB) if she has significant postmenopausal bleeding or unexplained irregular vaginal bleeding. This office biopsy allows endometrial cells to be examined under the microscope. To perform an endometrial biopsy, a speculum is inserted into the vagina, and a small flexible plastic tube is inserted through the cervix and into the uterus. A small amount of endometrium can be suctioned through the tube so the cells can be examined in a laboratory.


This sample will show whether cells are cancerous, and if so, what the grade of the cells is. Grade is assessed by how closely the cells resemble normal endometrial cells. A lower grade indicates more normal cells, and is associated with a better prognosis. Cancer cells can also be tested for progesterone receptors, which, if present in high numbers, indicate a better prognosis.


An endometrial biopsy is performed in a gynecologist’s office as an outpatient procedure. The discomfort is similar to brief but moderate-to-severe menstrual cramps.


A woman may undergo a procedure called dilation and curettage (D&C) if an endometrial biopsy cannot be performed in the office, or if she is strongly suspected to have cancer but had uncertain EMB results. A D&C is not necessary if the EMB already shows cancer. A D&C involves a thorough sampling of the endometrium, and thus is the most accurate test for endometrial cancer. The gynecologist dilates the cervix, and then scrapes the endometrium with a special instrument. A pathologist examines the tissue under a microscope.



The gynecologist may also view the endometrium with a fiber-optic scope, a procedure called hysteroscopy.
A D&C takes about one half-hour, is done on an outpatient basis, and usually requires either general anesthesia or sedation.
Although it can’t provide a conclusive diagnosis for endometrial cancer, a transvaginal ultrasound may provide clues about whether or not cancer is present. A transvaginal ultrasound is a test that is easily performed in the doctor’s office and allows the uterus to be seen. A special wand that uses ultrasound to create a picture is inserted into the vagina. A saline solution may be introduced through the vagina to enable the doctor to see the outline of the endometrium more clearly. The doctor can determine if the endometrium is abnormally thickened, and detect other abnormalities in the uterine wall.


After a diagnosis of endometrial cancer, other tests may be performed to get more information before surgery. Other tests may include:

• Chest x- ray for evidence of metastases to the lungs
• Pelvic and abdominal CT scan to check for metastases
• A blood test for CA-125 in women with possible advanced- stage endometrial cancer. CA-125 is a substance that is often found in gynecological cancers. The test may be used to monitor treatment progress, and may enable doctors to determine if cancer has recurred after treatment before symptoms arise

Prevention and Screening

Regular pelvic examinations and Pap smears are important for womens’ health, but do not usually detect endometrial cancer. Most doctors recommend that every woman over the age of 18 have an annual pelvic examination, which includes palpation of the uterus and ovaries by the doctor. A Pap smear is usually taken at the same time, which is an important test for early detection of cancer of the cervix. Pap smears are required annually unless otherwise specified by the doctor.


In some cases, cells from the endometrium are discovered during a Pap smear, and endometrial cancer can be detected on this basis. However, a Pap smear is not regarded to be an adequate screening or diagnostic test for endometrial cancer, and any woman who has abnormal bleeding, whether or not she has had a recent gynecological exam, should be checked by her doctor.


Using oral contraceptives significantly reduces the risk of endometrial cancer. Losing weight if you are overweight can help lower the risk of uterine cancer.


No general screening test is available for endometrial cancer.
Treatment

Self Care

A woman undergoing radiation treatment needs to stretch the vagina frequently to maintain the opening, both for ease of sexual intercourse and for maintaining the ability to undergo pelvic examinations without excessive pain. Narrowing of the vagina, also known as vaginal stenosis, is a common side effect of radiation. If possible, sexual intercourse three times a week can help prevent vaginal stenosis. As an alternative, doctors can prescribe special dilators to be inserted into the vagina for 10 to 15 minutes three times a week.


All women with cancer should take special care to attend to their emotional needs and maintain a healthy lifestyle. A diagnosis of cancer is always a difficult experience, and most women find it helpful to reach out to friends and family for support. Organized support groups through the hospital are also usually available.


Adopting and maintaining a healthy lifestyle is also important for enhancing one’s physical and mental well-being. If you are a smoker, ask your doctor for help in stopping. Limit alcohol to one to two drinks each day, and eat a healthy diet low in animal fat and with plenty of fresh fruits, vegetables, and whole grains. If you do not exercise regularly, ask your doctor about starting an exercise program.
Drug Therapy

Your doctor is the best source of information on the drug treatment choices available to you.
Other Therapies

Radiation to the pelvis is used in addition to surgery for many patients. Depending on the stage and grade of the disease, surgery may be all the treatment required. For others, radiation in addition to surgery has been shown to improve survival.


Radiation is used instead of surgery only in unusual circumstances. Radiation may be used instead of surgery when a woman’s general health is too poor to allow her to undergo surgery, of if cancer has spread so extensively that surgery may not be a valid option.
Radiation therapy can be delivered in different ways. External beam radiation is a common method. For external beam radiation, a beam of radiation is delivered to the body from a machine. Each treatment takes less than half an hour, and is required for four to six weeks, five days a week.


Radiation typically causes fatigue, and can damage the skin as well as other structures in the area being radiated. Many women experience pelvic discomfort and the frequent urge to urinate, a condition called “radiation cystitis”. Radiation can also irritate the intestines, especially the rectosigmoid colon, producing “radiation proctitis”. Narrowing of the vagina (vaginal stenosis) from scar formation can occur. Pelvic bones may be weakened, making a woman vulnerable to hip or pelvis fracture.
If the cancer remaining after surgery is confined to a small area, pellets of radiation can be implanted directly to the site. Applying radiation directly to the vagina is called brachytherapy.



It can be used to treat the upper vagina when it is believed that there is a risk that cancer can grow back after surgery. This is done when the tumor has grown to involve the lower part of the uterus (the cervix), for example. In most instances, this procedure can be done with a “vaginal cylinder”, which has radioactive material that is placed in the vagina for very brief periods of time. Indeed, there is now a technique of “high dose rate” brachytherapy, that is delivered in the outpatient setting over a period of just a few hours.


The side effects of this treatment may include vaginal discharge, irritation, and vaginal narrowing.
Surgery

A hysterectomy is performed for endometrial cancer in almost all cases. For some patients, it may be all the treatment required. A hysterectomy involves removing the uterus and cervix. In most women, the ovaries and fallopian tubes are also removed. For cancer caught in the earliest stage, only a hysterectomy may be necessary.



The uterus may be removed through an incision in the abdomen, or brought out through the vagina.
Typically during a hysterectomy, selected lymph nodes in the pelvis and the area around the aorta (the major artery that travels down the body) are removed and examined for cancer cells. If the surgery was done through the vagina, the lymph nodes can be removed through small incisions made in the abdomen.


A hysterectomy is an inpatient procedure requiring general or regional anesthesia. The hospital stay is typically three to four days for an abdominal procedure, and two to three days for a vaginal procedure. Complete recovery can be expected in four to six weeks.
Fallopian tubes and ovaries are also frequently removed to avoid the future possibility of cancer to the ovaries. This surgery is known as a bilateral salpingo-oophorectomy (BSO), and is often performed at the same time as a simple or radical hysterectomy. Removal of the ovaries induces menopause in premenopausal women.


Lymph nodes are removed to determine if the cancer has spread to them and to determine the stage of the cancer. During the hysterectomy, lymph nodes in the pelvis and around the aorta are sampled for cancer. If present, a lymph node “dissection” is performed, in which most or all of the nodes in the region are taken out.


A radical or modified radical hysterectomy may be necessary if the cancer has spread to the cervix. A radical hysterectomy (or modified radical hysterectomy) involves removing the uterus as well as the upper part of the vagina and the connective tissue adjacent to the cervix (parametrium), if necessary. A typical hospital stay is four or five days.


Premenopausal women with endometrial cancer undergo menopause after being treated with a hysterectomy and ovary removal. For women who have not yet entered menopause, the standard surgical treatment for endometrial cancer causes them to do so. Symptoms of menopause, including hot flashes, mood swings, and vaginal dryness, are typically more severe than for women who go through menopause more slowly and naturally.


Hormone replacement therapy can help to alleviate these symptoms. However, current guidelines state that estrogen alone (unopposed estrogen) can increase uterine cancer risk. Estrogen and progesterone combined have not been shown to increase this risk. Over-the-counter lubricants can also be used to alleviate vaginal dryness.
Surgery is not only essential for treatment, but also provides important information about the stage and prognosis of the disease, and guides further treatment decisions. Surgery allows doctors to stage the disease; that is, determine the cancer’s localized growth in the uterus and surrounding area, and discover whether there is evidence that it has spread. The doctors will:

• visually explore the female organs, the bladder, and the rectum
• cut open the uterus after it has been removed and determine how far into the muscle the cancer has spread
• remove lymph nodes from the pelvis and near the aorta
• sample fluid from the abdomen and pelvis
• remove other sites where the diseasehas spread if they are found

Table 1. Simplified Staging System for Endometrial Cancer

StageCharacteristicStage ICancer is present only in the uterus.Stage IICancer has spread to the cervix.Stage IIICancer has spread beyond the uterus, but is still confined to the pelvic area. Metastases may be present in the vagina and lymph nodes in the pelvis.Stage IVCancer has spread to the bladder or rectum. Metastases may be present in distant lymph nodes, bones or lungsSpecial Circumstances

Patients with stage III or IV disease or recurrent cancer may wish to consider joining a clinical trial to test new treatments for endometrial cancer. Clinical trials can give cancer patients access to potentially helpful new treatments. New medications are tested because it is believed that they may be better than standard treatment for the disease. For information about clinical trials, talk with your doctor and contact the Cancer Information Service at (800)-4-CANCER, or visit Welcome to the Centerwatch Clinical Trials Listing Service! and ClinicalTrials.gov - Information on Clinical Trials and Human Research Studies on the Internet.
Prognosis

Most women can be cured of endometrial cancer. The stage of the disease is the most important factor in determining prognosis. Fortunately, most cases of endometrial cancer are caught in the early stages of the disease when cure rates are high. Five-year survival rates for stage I disease are 70% to 95%. A five-year time period is used as a standard for statistical purposes, and most women can expect to be cured at that point and live a normal life span.


For stage III or IV, survival rates are 10% to 60%. Rates vary widely depending on individual circumstances.


The disease grade is another important factor. Grade of the disease is a measure of how abnormal the cancer cells appear under the microscope. Like stage, a lower grade has a better prognosis.
Younger women tend to have a better prognosis.
Endometrial cancers of cell types; e.g., serous carcinomas, tend to be more aggressive and carry a worse prognosis.
Follow-up

It is essential to set a schedule of follow-up visits during diagnosis, treatment, and recovery. Women should be seen frequently by their doctors while endometrial cancer is being diagnosed and treated, on a schedule determined by their individual circumstances. After treatment, women typically follow up with their doctors every three to six months, when the chance of recurrence is highest. After three years with no evidence of a recurrence, women typically follow up with their doctors every six months. Visits may include:

• a pelvic exam
• a Pap test
• a physical exam, with special attention feeling lymph nodes where cancer might spread
• a CA 125 blood test
• imaging tests such as CT scan or ultrasound

Women should report any pelvic pain following cancer treatment. Persistent pelvic pain could indicate a recurrence of the cancer or a fracture of a pelvic bone, particularly if a woman has had radiation therapy.