All About Endometrial (Uterine) Cancer

What is the endometrium?

The endometrium is the inner lining of the uterus. The uterus is an organ in the female pelvis. It is small, pear-shaped, and sits between a woman's rectum and her bladder (unless a woman is pregnant). The cervix is the name for the lowest part of the uterus. The cervix is the entrance to the uterus. 

There are two layers to the uterus: 

• The myometrium: The outer, muscular layer. 
• The endometrium: The inner lining that is made of thin tissue. 

Every month that you are fertile and not pregnant, your ovaries release an egg (called ovulation) that travels into your uterus and has the chance to become fertilized. During the few weeks leading up to ovulation, your endometrium thickens to provide a place for a fertilized egg to grow and develop. If the egg is not fertilized, the endometrial lining is shed. The endometrial lining and the unneeded blood supply pass through the birth canal (your vagina). This is called menstruation (your period). Two important hormones, estrogen and progesterone, help regulate your menstrual cycle and cause the endometrium to grow and thicken each month. If the egg is fertilized and you become pregnant, the baby grows and develops in your uterus. When pregnant, the uterus gets much bigger in size. 

What is endometrial cancer?

Endometrial cancer happens when cells in the endometrium begin to grow out of control. Large collections of these out-of-control cells are called tumors. Some tumors are called “benign” tumors. Benign tumors cannot spread throughout the body. The tumors that can spread throughout the body or grow into nearby tissues are called “malignant” tumors. 

It is important to know if a tumor in the endometrium is benign or malignant. There are many benign (non-cancerous) issues that can 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). Fibroids are not cancerous. They may cause increased vaginal bleeding, vaginal discharge, or pain. Your provider may suggest that you have your fibroids removed if they are causing issues.

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. This type makes up about 75% of all endometrial cancers. 
• The second most common form is papillary serous adenocarcinoma. This type makes up about 10% of all endometrial cancers. This type, as well as clear cell adenocarcinomas (listed below), tends to be more aggressive than endometrioid adenocarcinomas. They are often found at advanced stages.
• Another type is clear cell adenocarcinoma, which makes up about 4% of all endometrial carcinomas. This type, as well as papillary serous adenocarcinoma, tends to be more aggressive than endometrioid adenocarcinomas. They are often found at advanced stages.
• Sometimes an endometrial cancer has features of more than one subtype. This is called a mixed adenocarcinoma. 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 make up less than 1% of endometrial cancers.
• Another type of uterine cancer is sarcoma of the uterus, which is very rare. It makes up about 3% of all endometrial/uterine cancers. There are about 1600 cases each year. 
  • There are several subtypes of uterine sarcomas, including low grade endometrial stromal sarcoma (ESS), high grade ESS, undifferentiated uterine sarcoma (UUS) and uterine leiomyosarcoma (ULMS). 
  • There are also rare uterine mesenchymal sarcoma subtypes, including adenosarcoma, perivascular epitheliod cell tumor (PEComa), and rhabdomyosarcoma. Treatment for these rare uterine sarcomas often follows guidelines for soft tissue sarcoma. 

What causes endometrial cancer and am I at risk?

Endometrial cancer is the most common gynecological cancer in the United States. There are about 66,570 new cases of endometrial cancer diagnosed each year. There is a 2.8% chance of a woman developing endometrial cancer during her lifetime.

Most 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 old. Endometrial cancer is uncommon in women younger than 45 years of age. It appears to be slightly more common in Caucasian women, but women of other races tend to be diagnosed 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 is, the higher her chances are of getting endometrial cancer. Women who are exposed to more estrogen, either naturally or from outside sources, are more likely to develop endometrial cancer. Several things can affect how much estrogen a woman is exposed to. The more menstrual cycles a woman has in her lifetime, the more estrogen her endometrium is exposed to. Women who started menstruating at an early age, 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 more likely to develop endometrial cancer because their endometrium may be exposed to more estrogen over time.

Obesity is also a risk factor for endometrial cancer. Fat tissue converts other hormones into estrogens, so overweight people have higher levels of estrogen. Diabetes and high blood pressure (hypertension), which also tends to occur in obese people, may also be risk factors for endometrial cancer. 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 cancer coming back. Because it has estrogen-like properties, the use of tamoxifen is linked to higher rates of endometrial cancer. The risk is relatively small, and tamoxifen is prescribed because the relative benefits of taking it (in terms of breast cancer prevention) outweigh the increased risk of developing endometrial cancer.

Family history of endometrial cancer can also increase the risk 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. Lynch Syndrome is linked with a higher risk of colon and endometrial cancers (it is also called hereditary nonpolyposis colorectal cancer syndrome or HNPCC). Women can inherit a mutation from their parents. It may be beneficial to test for mutations if a woman has a 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 compared to 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 have more screening or even have a prophylactic hysterectomy (preventive removal of your uterus) to decrease her chances of developing cancer.

The decision to get tested is a highly personal one that should be discussed with a healthcare provider 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. However, this is hard to determine as many of the risk factors for breast and endometrial cancer overlap. There has not been any link 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 provider about your risk factors for endometrial cancer to understand his/her recommendations for screening and prevention.

How can I prevent endometrial cancer?

There are things you can do to prevent your chances of getting endometrial cancer. If you don’t have a family history/genetic syndrome, you can talk to your provider about: 

• Birth control (like OCPs - oral contraceptive pills, or Depo-Provera®). They stop ovulation/menstruation can reduce the risk of endometrial and ovarian cancer. The longer you take them, the more they help in this regard.
• Combined hormone replacement therapy. Medications with estrogen and progesterone appear to decrease the risk of endometrial cancer. 
• Exercise also seems to lower the risk of developing endometrial cancer.
• Healthy Diet: 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 (in soy products) and fatty fishes may decrease your risk, but further studies need to be done before these nutritional recommendations can be made regarding endometrial cancer prevention.
• Prophylactic Hysterectomy: If you are a carrier of Lynch Syndrome, you need to have more rigorous screening done for endometrial cancer. You may have your uterus removed when you are still healthy (called a prophylactic hysterectomy). This should only be done when you are finished having children. This procedure can eliminate the development of endometrial cancer. Before you decide to do this, you should have genetic testing and counseling from a provider who has experience with genetic diseases.

Ways to prevent endometrial cancer can be different for each person. Speak to your provider about the best ways for you. 

What screening tests are used for endometrial cancer?

Currently, 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.

Currently, the American Cancer Society recommends that you get an annual endometrial biopsy starting at age 35 if:

• You have Lynch Syndrome (HNPCC). 
• You have a family member with Lynch Syndrome. 
• You have a strong family history of colon cancer (even with negative genetic testing).

Endometrial biopsies can be done in your healthcare provider’s office. They are often the test a provider does when a post-menopausal patient has vaginal bleeding. Only women with a very high risk of getting endometrial cancer (patients with a genetic syndrome) should be screened in this way. Talk to your healthcare provider about your endometrial cancer risk, and whether or not you need to be screened.

Pre-menopausal women who have risk factors for endometrial cancer, such as tamoxifen or estrogen replacement therapy use, or who have bleeding between menstruations, should also be tested by a provider.

What are the signs of endometrial cancer?

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 if she has endometrial cancer. However, some of the other symptoms are non-specific, and they don’t always mean you have cancer. As a tumor grows in size, it can cause issues like:

• Vaginal bleeding (in a post-menopausal woman).
• Abnormal bleeding (including bleeding in between periods, or heavier/longer lasting than normal menstrual bleeding).
• Abnormal vaginal discharge (may be foul-smelling).
• Pelvic or back pain.
• Painful urination.
• Painful sexual intercourse.
• Blood in the stool or urine.
• Weight loss.

If you have any of these issues, you should contact your provider.

Many endometrial cancers are found at early stages because early endometrial cancers often cause vaginal bleeding (which is abnormal in postmenopausal women). If you are post-menopausal and have any vaginal bleeding, you should contact your provider as soon as possible. 

How is endometrial cancer diagnosed?

Endometrial cancer is diagnosed using an endometrial biopsy. A biopsy is the only way to know for sure if you have cancer. Your provider obtains cells that can be looked at under a microscope. Once the tissue is removed, a pathologist will review the specimen. The pathologist can tell if it is cancer or not. 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.

In most cases, a biopsy can be done in your healthcare provider’s office. A thin flexible tube is passed through your vagina and cervix and then into your uterus. A small amount of endometrium is removed. This can cause discomfort and anti-inflammatory medications can help with the pain. If your healthcare provider is not able to get enough endometrial tissue with an office biopsy, you will need to have a dilation and curettage (D & C). D&Cs are done in the operating room under anesthesia. Your healthcare provider dilates (opens up) the opening to your uterus and then removes endometrial tissue from the inside of the uterus. D&C is often done with the aid of a thin scope, known as a hysteroscope. This is so your healthcare provider can see the inside of the uterus and sample areas that look abnormal.

Another test that can help diagnose endometrial cancer is called the transvaginal ultrasound. Ultrasound is an imaging tool that uses sound waves that bounce off of tissues and provide a picture of whatever is being looked at. By inserting an ultrasound probe into a woman's vagina, the healthcare provider can look at the thickness of the endometrium. This test can determine if bleeding is being caused by a benign or malignant issue. If the endometrium appears too thick, then biopsies can be taken. It can be hard to determine if the thickening is due to cancer in premenopausal women, as they normally have a thicker endometrium. Another type of ultrasound, called sonohysterography, involves placing fluid in the uterus to get a better view of the endometrium.

How is endometrial cancer staged?

Endometrial cancer is usually staged and treated using a surgical procedure. Surgeons who specialize in gynecologic cancer look at the endometrium and send biopsy samples to a pathologist.

Surgery is needed for staging and your healthcare team may also order some tests to better characterize the tumor(s) and look for spread (metastasis). 

• Tests like CT (CAT) scans (a 3-D x-ray) or MRIs (like a CT scan but done with magnets) can look at the pelvis and nearby lymph nodes. 
• A chest X-ray may be done to see if there is a 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 the spread of the tumor to your colon and rectum. 
• Your healthcare provider may order a blood test called a CA-125, which if positive, predicts that there is a spread of cancer outside of your uterus. 

The tests you have will be specific to your case; but overall, your healthcare team wants to know as much about your tumor as possible so that they can plan the best available treatments.

In order to guide treatment and offer some insight into prognosis, endometrial cancer is staged into four different groups. The staging system used for endometrial cancer is the FIGO system (International Federation of Gynecologists and Obstetricians). These can be found at the end of this article. 

Healthcare providers also use the TNM system (also called tumor - node - metastasis system). 

• T- Describes the size and local invasiveness of the tumor.
• N- Describes which, if any, lymph nodes are involved.
• M- Describes if it has spread to other more distant areas of the body (metastasis). 

This is then interpreted as a stage somewhere from I (one) meaning more limited disease to IV (four), meaning more advanced disease.

The TNM breakdown is quite technical but is provided at the end of this article for your reference. Your healthcare provider will use the results of the diagnostic workup to assign the TNM result.

How is endometrial cancer treated?

Endometrial cancer is treated in a number of ways. Your provider will talk to you about your treatment options and what is best for you. 

Surgery 

Almost all women with endometrial cancer will have some type of surgery during the course of their treatment. There are two purposes of surgery:

1. To stage the cancer.
2. To remove as much of the cancer as possible. 

In early-stage cancers (stages I and II), surgeons can often remove all of the visible cancer. Often, women with endometrial cancer will have a hysterectomy (removal of the uterus) and bilateral salpingo-oophorectomy (removal of both ovaries and fallopian tubes). This is because there is always a risk of a small amount of disease in both the ovaries and the uterus. This surgery may be done with an abdominal (belly) incision or a laparoscopic approach. Laparoscopic surgery uses a small camera and smaller incisions to insert small instruments into the abdomen. Fluid is collected from the abdominal cavity during the surgery. Biopsies from other areas of the abdomen to look for malignant cells may also be done. The ovaries may be preserved (saved) in younger women with a low risk of ovarian involvement. Your surgeon will talk to you about your options. 

You may not have surgery is if you have a very early-stage cancer (IA) that looks favorable under the microscope (grade 1). If your tumor has these characteristics and you want the ability to have children, you may have other kinds of treatment. After you are done having children, you will need to have your 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 done in order to provide the best possible chance for a cure. Depending on 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.

If you have more advanced disease (stages III or IV), you will often have debulking surgery. This means that your surgeon will try to remove as much cancer as possible. If you have very advanced cancer, surgery may be used for palliation. This means that the goal is easing pain or symptoms, rather than trying to cure their disease. Talk to your surgeon about the exact type of operation you are going to have.

You should talk about all surgical side effects with your surgeon. Short-term side effects of surgery can include pain, infection, and damage to the bowel or bladder. Long-term side effects include intestinal obstruction (blockage) or lymphedema. Obstructions can be caused when scar tissue forms, trapping your intestines and stopping stool from moving 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, the lymph node drainage patterns can be altered, increasing the risk of lymphedema. The risk of lymphedema in the lower extremities following surgery for gynecologic cancers is about 20-45%.

Radiation

Radiation therapy uses high-energy x-rays to kill cancer cells. Endometrial cancer is often treated with radiation therapy in addition to surgery. Radiation is used to decrease the chances that the cancer will come back. Many trials have shown that adjuvant radiation (radiation given after surgery has removed the cancer) decreases local recurrence rates (cancer that returns in the same area). Radiation can also be used if you 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/EBRT) 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 to 6-8 weeks to a radiation therapy treatment center. The treatment takes just a few minutes and is painless. 
• Brachytherapy (also called intracavitary irradiation) allows your radiation oncologist to "boost" the radiation dose to the tumor. 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 calculates 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 place 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 procedure.

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.

For patients with more advanced disease, radiation is often given along with chemotherapy. Radiation can cause bowel irritation with diarrhea, and bladder irritation, which can cause frequent urination. In the long term, the vagina can form scar tissue, which can make intercourse and future gynecological exams uncomfortable or even painful. Because of vaginal dryness, lubrication may need to be used during sex following radiation. After the vaginal inflammation gets better after radiation, a vaginal dilator should be used several times a week. This can help keep the vagina open and prevent pain with sex and future gynecological exams. Radiation can also increase the risk of bowel obstruction and lymphedema as a result of scar tissue formation.

Chemotherapy

Chemotherapy is the use of anti-cancer drugs that go throughout the entire body. Chemotherapy is often used in endometrial cancers that are very advanced, or which have recurred after treatment with surgery and radiation. There are many different chemotherapy drugs and they are often given in combinations (regimens). Different chemotherapy regimens are used for different subtypes of uterine cancers. Some of the chemotherapies used in endometrial cancer include: cisplatin, carboplatin, doxorubicin, topotecan, ifosfamide, docetaxel,  olaratumab and paclitaxel. Based on your own health, your personal values and wishes, and side effects you may wish to avoid, you can work with your healthcare team to come up with the best regimen for your cancer and your lifestyle.

Hormonal Therapy 

When the pathologist looks at your tumor, they will see if the tumor is expressing estrogen and progesterone receptors. Hormone therapy may then be prescribed. Hormone therapy is only used for certain lower-grade types of endometrial cancer. Be sure to talk with your care provider if these are right for you. Medications used for hormone therapy include: megestrol, tamoxifen, fulvestrant, progestational agents such as hydroxyprogesterone and medroxyprogesterone, or aromatase inhibitors such as anastrozole, exemestane, and letrozole. 

Clinical Trials

There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. There are currently clinical trials investigating the use of targeted therapies to treat endometrial cancer. Clinical trials are extremely important in furthering our knowledge of the disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area.

You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Follow-up Care and Survivorship

Once you have been treated for endometrial cancer, you will need to be closely followed for a recurrence. It is recommended that you follow up with your healthcare team every three to six months for the first two years, then every year if everything appears normal. It is very important that you let your healthcare team know about any symptoms you are having and that you go to all of your follow-up appointments. The highest chance for a recurrence is in the first 3 years after diagnosis. 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). Most recurrences (70%) occur at the top of the vagina and cause symptoms such as vaginal bleeding, abdominal pain, or weight loss, and these should be reported to the healthcare provider right away. The longer you are free of disease, the less often you will have to go for checkups. Your healthcare team will tell you when you should have follow-up visits, pelvic ultrasounds, CA-125 levels and/or CT scans depending on your case. Your healthcare provider will also perform pelvic examinations during each of your office visits. During these pelvic exams, your healthcare provider may get samples of your cells to look for recurrent cancer.

Fear of recurrence, relationships and sexual health, the financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by endometrial cancer survivors. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With almost 17 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

Foundation for Women’s Cancers 

Offers comprehensive information by cancer type that can help guide you through your diagnosis and treatment. Also offers the ‘Sisterhood of Survivorship’ to connect with others facing similar challenges.

www.foundationforwomenscancer.org/

Cancer Care

Provides education, resources, and support both online and by phone.

www.cancercare.org

Appendix: Complete Endometrial Cancer Staging

Surgical Staging Systems for Endometrial Cancer

American Joint Committee on Cancer (8.2018) and International Federation of Gynecology and Obstetrics (FIGO), 2018.

(Suffix “sn” is added to the N category when metastasis is identified only by sentinel lymph node biopsy.)

Surgical Staging Systems for Uterine Sarcoma 

American Joint Committee on Cancer (8.2018) and International Federation of Gynecology and Obstetrics (FIGO), 2018).