Christopher Dolinsky, MD
Edited by: J Taylor Whaley
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: August 5, 2013
The endometrium is the inner layer lining the uterus. The uterus is an organ in the female pelvis, and it is where a baby grows and develops when a woman is pregnant. During pregnancy, the uterus undergoes an enormous increase in size. When a woman is not pregnant, the uterus is a small, pear-shaped organ that sits between a woman's rectum and her bladder. The cervix is the name for the lowest part of the uterus, and serves as the entrance to the uterus. There are two layers to the uterus: the myometrium, which is the outer, muscular layer, and the endometrium, the inner lining. Every month that a woman is fertile and not pregnant, her ovaries release an egg that travels into her uterus and has the potential to become fertilized. During the few weeks leading up to an ovulation, a woman's endometrium thickens to provide a place for a fertilized embryo to grow and develop. If the egg is not fertilized, the endometrial lining is shed and together with the unneeded blood supply is passed through the birth canal (the woman's vagina). This is called menstruation. Two very important hormones, estrogen and progesterone, help regulate a woman's menstrual cycle and cause the endometrium to grow and thicken each month.
Endometrial cancer develops when cells in the endometrium begin to grow out of control and can then invade nearby tissues or spread throughout the body. Large collections of this "out of control" tissue are called tumors. However, some tumors are not true cancers because they cannot spread or threaten someone's life. These are called benign tumors. The tumors that can spread throughout the body or invade nearby tissues are considered true cancers and are generally called malignant tumors. The distinction between benign and malignant tumors is very important in uterine cancer because there are many benign processes, which affect the uterus and may be confused for cancers. Fibroids (also called uterine myomas) are very common benign tumors of the muscle of the uterus (myometrium), which are not cancerous. They can occasionally cause increased vaginal bleeding, vaginal discharge, or pain. Your doctor may suggest that you have your fibroids removed if they are becoming bothersome.
Cancers are characterized by the normal cells from which they form. The most common type of endometrial cancer is called endometrioid adenocarcinoma; it comes from cells that form glands in the endometrium, and it has a characteristic appearance under the microscope. Endometrioid endometrial cancer compromises about 75-80% of all endometrial cancers. The second most common form is papillary serous adenocarcinoma (about 10% of all endometrial cancers), and yet another form is clear cell adenocarcinoma (about 4-5% of all endometrial carcinomas). Both papillary serous and clear cell adenocarcinomas tend to be more aggressive than endometrioid adenocarcinomas, and are often detected at advanced stages. Sometimes an endometrial cancer has features of more than one subtype; this is called a mixed adenocarcinoma and they make up about 10% of all endometrial cancers. There are a few other rare types like mucinous adenocarcinoma and squamous cell adenocarcinoma that each account for than 1% of endometrial cancers.
Endometrial cancer is the most common gynecological malignancy in the United States. There will be an estimated 49,500 new cases diagnosed and 8,000 deaths attributed to endometrial cancer in 2013. There is a 2.6% chance of a woman developing endometrial cancer during her lifetime and it causes approximately 6% of all cancers in women.
The majority of women diagnosed with endometrial cancer have already gone through menopause, although it can occur in younger women as well. The average age of diagnosis is around 60 years of age. Endometrial cancer is uncommon in women less than 40 years of age (5-10% of cases). It appears to be slightly more common in Caucasian women, but women of other races tend to present with more advanced disease.
Although there are several known risk factors for getting endometrial cancer, no one knows exactly why one woman gets it and another doesn't. One of the risk factors for developing endometrial cancer is age; the older a woman becomes, the higher her chances are of getting it. There appear to be two types of endometrial cancers: type I, which is estrogen-related and is more common (80% of cases), and type II, which does not appear to be estrogen-related and tends to present with more aggressive disease. For women with type I endometrial cancer, it appears that the amount of estrogen that a woman is exposed to in her lifetime influences her chances of contracting endometrial cancer. Women who are exposed to more estrogen, either naturally or from outside sources, are more likely to develop endometrial cancer. Thus, any factor that causes a woman to have high levels of estrogen is also a risk factor for endometrial cancer. The more menstrual cycles a woman has in her lifetime, the more estrogen to which her endometrium is exposed. Women who started menstruating early, go through menopause late, don't have any children, don't breastfeed, or don't use a form of birth control that stops ovulation (like birth control pills) are all potentially more likely to develop endometrial cancer. Another condition that increases estrogen in a woman's body is obesity. Fat tissue converts other hormones into estrogens, so overweight people have higher levels of estrogen than thin people. This means that obesity is also a risk factor for endometrial cancer. Diabetes and high blood pressure (hypertension) (which also tends to occur in obese people) appear to be risk factors for endometrial cancer as well. Women who take hormone replacement therapy (HRT) after menopause are at a slightly increased risk for endometrial cancer. Tamoxifen is a drug that is used in women with breast cancer to decrease their risk of a cancer recurrence. Because it has estrogen-like properties, the use of tamoxifen is linked to higher rates of endometrial cancer. However, the danger is relatively small and tamoxifen is prescribed because the relative benefits of taking it (in terms of breast cancer prevention) outweigh the apparently minor increased risk of developing endometrial cancer.
Another risk factor for endometrial cancer is a family history of endometrial cancer. The greatest risk appears to be in first-degree relatives (direct family members). A small percentage of women who get endometrial cancer carry a genetic mutation called Lynch Syndrome, which is associated with higher risk of colon and endometrial cancers (it is also called hereditary nonpolyposis colorectal cancer syndrome - HNPCC). Women can inherit a mutation from their parents and it may be worth testing for mutations if a woman has a particularly strong family history of endometrial or colon cancer (meaning multiple relatives affected, especially if they are under 50 years old when they get the disease). Having a mutation doesn't necessarily mean a woman is going to get the disease, but it does greatly increase her chances above the general population. Family members may elect to get tested to see if they carry mutations as well. If a woman does have the mutation, she can get more rigorous screening or even undergo a prophylactic hysterectomy (preventive removal of your uterus) to decrease her chances of contracting cancer. The decision to get tested is a highly personal one that should be discussed with a doctor who is trained in counseling patients about genetic testing. People with a history of breast cancer may also be at increased risk for endometrial cancer, but this is difficult to determine as many of the risk factors for breast and endometrial cancer overlap. As of yet, there has not been any association found between genes associated with breast cancer, such as the BRCA1 gene, and endometrial cancer, though studies are ongoing.
It has been demonstrated that a diet high in animal fats and low in fruits and vegetables can increase your risk for endometrial cancer. Remember that all risk factors are based on probabilities, and even someone without any risk factors can still get endometrial cancer. Talk to your doctor about your risk factors for endometrial cancer to understand his/her recommendations for screening and prevention.
Unfortunately, there aren't very good screening methods for endometrial cancer, so preventing it is a particularly important challenge. If you are a woman without a family history/genetic syndrome, there are some things which are under your control and which can reduce the risk of endometrial cancer Birth control (like OCPs - oral contraceptive pills, or depo-provera) that stop ovulation/menstruation can reduce the risk of developing both endometrial and ovarian cancer. Multiple studies have demonstrated that OCPs reduce a woman's risk for developing endometrial cancer; the longer a woman takes them, the more they help in this regard. Combined hormone replacement therapy with both an estrogen and a progesterone component also appears to decrease the risk of endometrial cancer. However, both birth control and combined hormone replacement have several side effects so consult with your physician to see if they are right for your specific situation. Exercise also appears to reduce the risk of developing endometrial cancer.
While a diet high in animal fats has been implicated in endometrial cancer, a diet rich in fruits and vegetables may have a small preventive effect. It has been suggested that diets high in naturally occurring phytoestrogens (which are prevalent in soy products) and fatty fishes may decrease your risk, but further studies need to be performed before these particular nutritional recommendations can be made regarding endometrial cancer prevention.
Women who are carriers of Lynch Syndrome, the above mentioned genetic syndrome, face different decisions. They generally need to have more rigorous screening done for endometrial cancer, and some of them may elect to have their uterus's removed when they are still healthy (called a prophylactic hysterectomy). This should only be done when a woman is finished having children, and it can eliminate the possibility that a woman will contract endometrial cancer. Before a woman decides to do this, she should have genetic testing and a significant amount of counseling from a physician who has experience with genetic diseases. Another time that some women will be offered a prophylactic hysterectomy is if they are done having children, have already gone through menopause, and are taking estrogens as a part of hormone replacement therapy. Discuss your options with your doctors to best sort out the different methods of preventing endometrial cancer in your particular case.
Patients who are diagnosed with early endometrial cancers tend to respond to treatment better than patients with more advanced cancers, so it is beneficial to detect endometrial cancers as early as possible. Luckily, many endometrial cancers are found at early stages, because early endometrial cancers often cause vaginal bleeding (which is very abnormal in post-menopausal women). When post-menopausal women experience vaginal bleeding, they are often worried enough to see their physicians who can then use more invasive tests to look for endometrial cancers. Remember, all postmenopausal vaginal bleeding should be brought to a physician's attention as soon as possible. The amount of bleeding does not correlate with the risk of cancer, so even a small amount of bleeding should be investigated. Additionally, pre-menopausal woman, who have risk factors for endometrial cancer, such as tamoxifen or estrogen replacement therapy use, who have bleeding between menstruations, should also be evaluated by a physician.
Right now, there aren't any endometrial cancer screening recommendations for the general population (women without hereditary cancer syndromes) because there aren't any effective screening tests available. Women should get annual pelvic exams for cervical and ovarian cancer screening, but endometrial cancer is not routinely screened for in the general population.
Women with a strong family history and many risk factors or who have a proven hereditary cancer syndrome may need to get rigorous screening for endometrial cancer. Currently, the American Cancer Society recommends that women, who have Lynch Syndrome (HNPCC) or, who have a family member with Lynch Syndrome, or, who have a strong family history of colon cancer (even with negative genetic testing), get annual endometrial biopsies starting at age 35. Endometrial biopsies can be done in your doctor's office. They are often the first step a doctor takes when a post-menopausal patient has vaginal bleeding. However, only women with a very high risk for getting endometrial cancer, (like patients with a genetic syndrome), should be screened in this manner. Talk to your doctor about your endometrial cancer risk, and whether or not you need to be screened.
Luckily, the early stages of endometrial cancer can cause symptoms. When a post-menopausal woman has vaginal bleeding (present in 90% of women at the time of diagnosis with endometrial cancer), the first thing that needs to be looked into is the possibility of endometrial cancer. However, some of the other symptoms are occasionally non-specific, and don't always point toward a diagnosis of endometrial cancer. As a tumor grows in size, it can produce a variety of problems including:
All of these symptoms are non-specific, and could represent a variety of different conditions; however, your doctor needs to see you if you develop any of these problems.
When a post-menopausal woman has new onset vaginal bleeding, or any woman has symptoms that suggest a possibility of endometrial cancer, their doctors will want to get a sample of their endometrium called an endometrial biopsy. A biopsy is the only way to know for sure if you have cancer, because it allows your doctors to get cells that can be examined under a microscope. Once the tissue is removed, a doctor known as a pathologist will review the specimen. The pathologist can tell if it is cancer or not; and if it is cancerous, then the pathologist will characterize it by what type of tissue it arose from and what subtype of cancer it is, how abnormal it looks (known as the grade), and whether or not it is invading surrounding tissues.
The least invasive method to get a biopsy is to do it in your doctor's office. A thin flexible tube is passed through a woman's vagina and cervix and then into her uterus. A small amount of endometrium is removed; this can be somewhat uncomfortable and sometimes anti-inflammatory medications can help with the pain. Occasionally, your doctor will not be able to get enough endometrial tissue with an office biopsy. In this case, you will need to have a dilation and curettage (D & C). D&Cs are done in the hospital, in the operating room under anesthesia. Your doctor dilates the opening to your uterus and then removes endometrial tissue from the inside of the uterus, which can then be sent to a pathologist to be studied under a microscope. The D & C is often done with the aid of a thin scope, known as a hysteroscope, so your doctors can see the inside of the uterus and specifically sample areas that appear abnormal.
Another technique that can help make the diagnosis of endometrial cancer is called transvaginal ultrasound. Ultrasound is an imaging modality that uses sound waves that bounce off of tissues and provide a picture of whatever is being investigated. By inserting an ultrasound probe into a woman's vagina, doctors can get a pretty good look at the thickness of her endometrium. This technique can help differentiate benign (non-cancerous causes of bleeding) from malignant causes of bleeding. If the endometrium appears too thick, then biopsies can be taken. However, it may be more difficult to determine if the thickening is due to cancer in premenopausal women, as they normally have a thicker endometrial stripe. Another type of ultrasound known as a sonohysterography involves placing fluid in the uterus to get a better view of the endometrial stripe.
Endometrial cancer is a type of cancer that needs to be staged during a surgery; it is usually staged and treated during the same operation. In order to guide treatment and offer some insight into prognosis, endometrial cancer is staged into four different groups at the time of the surgery. Surgeons who specialize in gynecologic malignancies go through a careful inspection and sampling of a woman's pelvis during this procedure, and biopsy specimens are sent to a pathologist while the surgeon is still working. The staging system used for endometrial cancer is the FIGO system (International Federation of Gynecologists and Obstetricians). The staging system is somewhat complex, but here is a simplified version of it:
Generally, the higher the stage, the more serious the cancer is. Although surgery is required for staging, your physicians may want to order some other tests to better characterize the mass/masses and look for distant spread. Tests like CT (CAT) scans (a 3-D x-ray) or MRIs (like a CT scan but done with magnets) can examine the pelvis and localized lymph nodes. A chest X-ray is also sometimes used to determine if there is spread of disease to the chest. You may get also get a colonoscopy, which uses a lighted scope to examine your rectum and colon, or a barium enema in which dye is inserted into your rectum and an x-ray is taken. These tests are to look for spread of the tumor to your colon and rectum. Your doctor may order a blood test called a CA-125, which if positive, predicts that there is spread of the cancer outside of your uterus. Each patient is an individual so the specific tests people get will vary; but overall, your doctors want to know as much about your particular tumor as possible so that they can plan the best available treatments.
What are the treatments for endometrial cancer?
Almost all women with endometrial cancer will have some type of surgery in the course of their treatment. The purpose of surgery is first to stage the cancer, and then to remove as much of the cancer as possible. In early stage cancers (stage I and II), surgeons can often remove all of the visible cancer. Generally, women with endometrial cancer will have a hysterectomy (removal of the uterus) and bilateral salpingo-ooporectomy (removal of both ovaries and fallopian tubes) as part of their operation. This is because there is always a risk of microscopic disease in both of the ovaries and the uterus. This surgery is usually done with an abdominal incision; however, laproscopic surgery has become very common in modern practice. This utilizes a small camera and smaller incision to insert small instruments into the abdomen. The abdominal cavity is carefully inspected and fluid is collected from the abdominal cavity during the surgery. Biopsies from other area of the abdomen to look for malignant cells may also be collected. Rarely, it may be recommended that the ovaries be preserved in younger women with a low risk of ovarian involvement. This strategy requires an in-depth discussion with your surgeon. The only circumstance in which a woman may not have an operation is if she has a very early stage cancer (IA) that looks favorable under the microscope (grade 1). If a woman's tumor has these characteristics and she desires to maintain the ability to have children, then she can be treated by other modalities. Then after she is done having children, she will need to have her uterus, fallopian tubes and ovaries removed. With any other stage or grade of tumor, or in patients finished with childbearing, the entire operation should be performed in order to provide the best possible chance for a cure. Depending on the particulars of your case, your surgeon may also remove pelvic lymph nodes during the operation to look for possible cancer spread. Testing the nodes for cancer is very important as it helps direct additional treatment after surgery.
Women who have more advanced disease (stage III or IV) will often have debulking surgeries, which means that their surgeon will attempt to remove as much disease as possible. Data collected in many studies has demonstrated that the more tumor that it debulked, the better the long term outcome for the patient. Operations for endometrial cancer should be performed by surgeons who are trained in dealing with gynecologic malignancies because there are special skills and techniques necessary to deal with these tumors. In patients with very advanced cancers, surgery may be used for palliation- meaning that patients are operated on with the intent of easing their pain or symptoms, rather than trying to cure their disease. Talk to your surgeons about exactly type of operation you are going to undergo.
Surgery can have side effects that should be discussed with your surgeon. In the short term, surgery is associated with risks of pain, infection, and damage to the bowel or bladder. In the long term, surgery can be associated with an intestinal obstruction or lymphedema. Obstructions can be caused when scar tissue forms, trapping your intestines and preventing the passage of stool through the bowel. Lymphedema is caused by a build-up of fluid that our bodies normally filter as part of our immune systems. When surgery is performed and lymph nodes are removed for a cancer operation, the lymph node drainage patterns can be altered, increasing the risk of lymphedema. The risk of lymphedema in the lower extremities following oncologic surgery for gynecologic cancers is approximately 20%.
Endometrial cancer is commonly treated with radiation therapy as well as surgery, and radiation has proven very effective in management through its prevention of local recurrences. Numerous randomized trials have demonstrated that adjuvant radiation (radiation given after surgery has removed the cancer) significantly decreases local recurrence rates (cancer that returns in the same area). Radiation therapy uses high energy x-rays to kill cancer cells. Radiation is usually offered after an operation as an adjuvant therapy to the surgery. Radiation is generally used in all but the most favorable cases (very early stages with low grades, and little invasion). Radiation is used to decrease the chances that the cancer will come back. Radiation can also be used in place of surgery in patients who are too ill to risk having anesthesia, but the best results come from the combination of both surgery and radiation.
Radiation therapy for endometrial cancer either consists of x-rays delivered from the outside of the patient (external beam radiation) or from a radioactive source placed inside the vagina (brachytherapy). External beam radiation therapy requires patients to come in 5 days a week for up 6-8 weeks to a radiation therapy treatment center. The treatment takes just a few minutes, and is painless. Usually, patients will also be offered internal brachytherapy. Brachytherapy (also called intracavitary irradiation) allows your radiation oncologist to "boost" the radiation dose to the tumor bed. This provides an added impact while sparing your normal tissues. This is done by inserting a hollow tube into your vagina. Then a small radioactive source is placed in the tube. A computer has calculated how long the source needs to be there, but usually for what is called low dose rate (LDR) brachytherapy, you will need to have the source in for a few days. This procedure is done in the hospital, because for those few days you have to remain in bed. Another type of brachytherapy, called high dose rate (HDR) brachytherapy, uses more powerful sources that only stay in for a few minutes. HDR can be performed as an outpatient. Based on the results of your surgery, pathology results, and imaging, your radiation oncologist may recommend brachytherapy alone, brachytherapy with chemotherapy, external beam radiation alone, or may recommend a combination of these, depending on your situation. Depending on your stage, radiation is used after surgery as studies have shown it significantly decreases the risk of the tumor recurring within the pelvis. For patients with early stage disease, a randomized trial of patients with early stage high-intermediate risk endometrial cancer demonstrated external beam radiation decreased the risk of recurrence from 26% to 6%. Additional randomized studies have found that for certain patients, brachytherapy may be nearly as effective as external beam, with fewer associated side effects. For patient with more advanced disease, radiation is frequently given along with chemotherapy. Radiation can cause bowel irritation with diarrhea and bladder irritation, which can cause frequent urination. Additionally, in the long term, the vagina can form scar tissue, which can make intercourse painful. Frequently, because of vaginal dryness, lubrication may need to be utilized during sex following radiation. After the acute vaginal inflammation resolves following radiation, a vaginal dilator should be used several times a week, for life (or alternatively, regular intercourse), to reduce the severity of scar tissue formation and problems that can result from vaginal scarring. This helps to make the necessary regular pelvic exams more comfortable and allow the physician to view the areas more fully. Radiation can also increase the risk of bowel obstruction and lymphedema as a result of scar tissue formation.
Chemotherapy is the use of anti-cancer drugs that go throughout the entire body. Although chemotherapy has traditionally had a smaller role in endometrial cancer, it is frequently employed in endometrial cancers that are very advanced, or which have recurred after definitive treatment with surgery and radiation. There are many different chemotherapy drugs, and they are often given in combinations. Patients will usually have to go to a clinic to get the chemotherapy because many of the drugs have to be given through a vein. Different chemotherapy regimens are used for different purposes. Some of the drugs used in endometrial cancer chemotherapy include: Cisplatin, Carboplatin, Doxorubicin, and Paclitaxel. There are advantages and disadvantages to each of the different regimens that your medical oncologist can discuss with you. Based on your own health, your personal values and wishes, and side effects you may wish to avoid, you can work with your doctors to come up with the best regimen for your cancer and your lifestyle.
When the pathologist examines your tumor specimen, he or she determines if the tumor is expressing estrogen and progesterone receptors. Patients whose tumors express progesterone receptors are candidates for therapy with progesterone; agents such as hydroxyprogesterone and medroxyprogesterone. These medications are usually used in patients with very advanced or recurrent endometrial cancers when they are not healthy enough to undergo surgery or radiation.
Once a patient has been treated for endometrial cancer, they need to be closely followed for a recurrence. At first, you will have follow-up visits fairly often. The highest chance for a recurrence is in the first 3 years after diagnosis. Not surprisingly, the highest risk of recurrence is in those women who had high-risk disease. In women with low risk disease, there tends to be a very small risk of recurrence (less than 5%). About 40% of recurrences are local (near where the tumor was) and 60% are distant (to other organs). The majority of recurrences (70%) occurs at the top of the vagina and cause symptoms such as vaginal bleeding, abdominal pain, or weight loss, and should be reported to one's physician immediately if they occur. The longer you are free of disease, the less often you will have to go for checkups. Your doctor will tell you when he or she wants follow-up visits, pelvic ultrasounds, CA-125 levels and/or CT scans depending on your case. Your doctors will also perform pelvic examinations during each of your office visits. During these pelvic exams, your doctors may get samples of your vaginal cells to look for recurrent cancer. Generally, it is recommended that you follow up with your physician every three to six months after being treated for the first two years then annually, if everything appears normal. It is very important that you let your doctor know about any symptoms you are experiencing and that you keep all of your follow-up appointments.
Clinical trials are extremely important in furthering our knowledge of this disease. It is though clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your doctor about participating in clinical trials in your area.
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