Endometrial Cancer

What is Endometrial Cancer?

Endometrial cancer, also known as uterine or womb cancer, is a type of cancer that begins in the uterus. The uterus is a hollow, pear-shaped pelvic organ where the development of a baby takes place during pregnancy. At the end of the uterus is the cervix, which connects the uterus to the vagina. Endometrial cancer begins in the layer of cells that form the lining of the uterus (known as the endometrium).

Types of Endometrial Cancers

Endometrial cancers can be grouped according to how aggressive they are^1,2,3:

• Type 1 endometrial cancers are less aggressive. They tend not to spread to other tissues quickly and usually have a better outcome. Most endometrial cancers are of a subtype known as endometrioid adenocarcinoma. Type 1 endometrial cancers are thought to be caused by too much oestrogen.
• Type 2 endometrial cancers are more aggressive. These include rarer subtypes, such as serous, clear cell, mucinous, undifferentiated and dedifferentiated carcinomas. They tend to grow faster and are more likely to spread outside the uterus by the time they are diagnosed. These cancers do not look like normal endometrium and so are called poorly differentiated or high-grade.

How Common is Endometrial Cancer?

In Singapore, uterine cancer (including endometrial cancer and other much rarer types of uterine cancers) is the fourth most common cancer detected in women⁴. It is the most common cancer of the female reproductive organs and is more frequently diagnosed in women who have gone through menopause⁵.

The good news is that the number of deaths from uterine cancer is relatively low compared to most of the other top ten cancers. This is because it usually shows symptoms early in the disease process, which allows for prompt diagnosis and treatment before the cancer has spread.

What causes Endometrial Cancer?

Endometrial cancer happens when cells in the endometrium develop changes (mutations) in their DNA that cause the endometrial cells to grow abnormally and develop into a tumour. The exact trigger for the mutations is not fully known.

Endometrial Cancer Risk Factors

Doctors may not always have an explanation as to why one person develops endometrial cancer, and another does not. However, there are certain risk factors that increase the likelihood of a person developing endometrial cancer, including^1,2,6:

• Hormonal factors: An imbalance of the two main female hormones (oestrogen and progesterone) can affect the endometrium, making cancer more likely to develop. The growth of the cancer cells is usually stimulated by oestrogen, which is a hormone produced by the ovaries as well as fat cells in the body. A woman's risk of developing endometrial cancer is increased by prolonged stimulation and exposure to oestrogen. These include conditions and situations such as:
  • Obesity: A woman's ovaries is the main producer of oestrogen before menopause. However, fat tissue can change some other hormones (called androgens) into oestrogens. This can affect oestrogen levels, especially after menopause. The higher the fat tissue amount, the greater the increase in oestrogen levels, and therefore the higher the risk for developing endometrial cancer. Compared to women who stay at a healthy weight, endometrial cancer is twice as common in overweight women (measured as a Body Mass Index or BMI of 25 to 30), and more than 3 times as common in obese women (BMI > 30)⁶. Gaining weight as you get older and having frequent weight fluctuations during your lifetime have also been associated with a higher risk of endometrial cancer after menopause6.
  • Having more menstrual cycles during a woman's lifetime: Having more menstrual periods exposes the endometrium to more oestrogen, therefore early menstruation before age 12 and/or late menopause after age 50 increases the risk for endometrial cancer.
  • Having few or no pregnancies: The hormonal balance shifts toward more progesterone during pregnancy which offers protection against endometrial cancer6. Women who have never been pregnant have a higher risk of developing endometrial cancer.
  • Hormone replacement therapy with oestrogen: Oestrogen treatment is used to relieve menopausal symptoms such as hot flashes and vaginal dryness, and help prevent osteoporosis (weakening of the bones) that can occur with menopause. However, using oestrogen alone without progesterone can lead to endometrial cancer. A hormone therapy medicine that combines estrogen and progestin, called combination hormone therapy, can lower this risk.
  • Ovarian diseases: Certain ovarian tumours produce high levels of oestrogen causing a hormonal imbalance which increases the risk for endometrial cancer. Women with a condition called polycystic ovarian syndrome (PCOS) have abnormal hormone levels, such as higher androgen (male hormones) and oestrogen levels and lower progesterone levels. The hormonal imbalance leads to irregular menstrual cycles, infertility and an increased likelihood of getting endometrial cancer.
  • Hormone therapy for breast cancer: Women taking certain hormonal drugs (such as tamoxifen) to treat or prevent breast cancer have an increased risk of developing endometrial cancer. However, it is important to weigh this risk against the benefits of reducing the chance of breast cancer recurring (coming back).
• Age: Endometrial cancer is most commonly diagnosed in women in their 50s and 60s, when they have undergone menopause.
• Diet: A diet high in animal fats can increase the risk of many cancers, including endometrial cancer. Fatty foods are also usually high-calorie foods which can lead to obesity, a well-known endometrial cancer risk factor.
• Endometrial hyperplasia: Endometrial hyperplasia occurs when there is increased growth of the endometrium resulting in a thickened lining. It is most commonly a mild or simple hyperplasia which has a very small risk of becoming cancer. If the hyperplasia is considered atypical, it has a higher chance of developing into cancer if it is not treated.
• Previous breast or ovarian cancer: Women who had breast or ovarian cancer may also develop endometrial cancer. These cancers have common dietary, hormonal, and reproductive risk factors.
• Type 2 diabetes: Endometrial cancer is about twice as common in women with type 2 diabetes compared to someone without diabetes.
• Family history: Having a family history of endometrial cancer in a first-degree relative (mother, sister, or daughter) increases your likelihood of also getting it. Some inherited conditions such as hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by a genetic mutation that is passed from generation to generation. If an individual has this syndrome, there is an increased risk of other cancers, including up to a 70% risk of developing endometrial cancer⁶.
• Previous pelvic radiation therapy: Radiation therapy to the pelvis to treat other cancers can cause damage to normal cell DNA. This damage may increase your risk of developing a second type of cancer in the pelvic organs, including the uterus.

Having one or more of these risk factors does not automatically mean that you will get endometrial cancer. Many people with risk factors never develop endometrial cancer, whilst some with no known risk factors do.

What are the Signs and Symptoms of Endometrial Cancer?

Signs and symptoms of endometrial cancer include⁷:

• Abnormal vaginal bleeding including bleeding between periods, bleeding more than once a month, continuous bleeding or spotting throughout the month and bleeding after menopause.
• Abnormal vaginal discharge which may be watery, blood-tinged or brownish and foul smelling.
• Pelvic cramping or pain.
• An enlarged pelvic mass.
• Unexpected weight loss.
• Pain during sexual intercourse.
• Bleeding after sexual intercourse.
• Difficult or painful urination.

Early detection of endometrial cancer leads to a higher chance of a good outcome and cure. If you have any of these symptoms, you should see a doctor promptly to be checked out and treated if needed.

Diagnosis of Endometrial Cancer

Endometrial cancer is often detected at an early stage because it presents as abnormal vaginal bleeding, especially bleeding after menopause. If endometrial cancer is suspected, your doctor will investigate further to determine if you have cancer^1,8:

• Clinical history and examination: Your doctor will ask about symptoms, risk factors and family history as well as perform a physical and pelvic examination. During a pelvic examination, your doctor will check the inside of the vagina and cervix to look for any abnormalities. The size and shape of the uterus and ovaries will also be assessed for any tenderness or enlarged areas.
• Blood tests: Blood tests may show certain proteins called tumour markers that are produced by cancer cells. One tumour marker test used in endometrial cancer diagnosis is called CA-125. A very high CA-125 indicates that the cancer has likely spread beyond the uterus. Doctors may repeat this test during and after treatment to understand how the cancer is responding. Some endometrial cancers do not make CA-125, so this test is not helpful for everyone. Other blood tests are also done to check your general health and how your kidneys and liver are functioning.
• Transvaginal ultrasound: Ultrasound scans use high-frequency sound waves to create images of the female organs. A wand-like device called a transducer is inserted into your vagina to see if there is any mass in the uterus or thickening of the endometrium which may be cancer.
• Hysteroscopy: This involves the insertion of a small thin, lighted tube with a camera at the tip (scope) through the vagina and cervix into your uterus. This allows the doctor to examine the cervix, the inside and the lining of the uterus.
• Endometrial biopsy: This involves removing tissue from the endometrium for analysis. This can be done during a hysteroscopy. If insufficient tissue is obtained, a small procedure called dilatation and curettage (D&C) will be recommended. In this procedure, the endometrial tissue is scraped and sent for analysis. This is usually done in an outpatient setting. The tissue sample is analysed in a laboratory to determine whether cancer cells are present, and if so, what type of endometrial cancer and grade it is (described further below). Genetic testing may also be done on the cancer cells to look for specific protein or gene changes which can influence treatment choice.

How is Endometrial Cancer Assessed?

After endometrial cancer has been diagnosed, your doctor will determine the extent (stage) of the disease. Staging, usually done with CT scans, PET-CT scans or MRI, is done to find out whether the cancer has spread, and if so, to what parts of the body. Endometrial cancer spreads most often to nearby lymph nodes, bladder and rectum, and then to the liver, lungs and bone.

Endometrial cancer can be grouped according to grade. The grade of an endometrial cancer is based on how much the cancer cells are organised into glands that look like those found in a normal, healthy endometrium³:

• Grade 1 tumours have 95% or more of the cancer cells forming glands.
• Grade 2 tumours have 50% to 94% of the cancer cells forming glands.
• Grade 3 tumours have less than 50% of the cancer cells forming glands with most of the cells disorganised and not resembling normal endometrial cells. Grade 3 cancers are also called poorly differentiated or high-grade tumours. They tend to be aggressive (they grow and spread fast) and have a poorer outlook than lower-grade cancers.

The stages of endometrial cancer are⁹:

• Stage I: Cancer is confined to the uterus.
• Stage II: Cancer has extended from the uterus to the cervix.
• Stage III: Cancer has extended beyond the uterus but has not involved the rectum and bladder. It may have spread to the pelvic lymph nodes.
• Stage IV: Cancer has spread beyond the pelvic region and extended to other organs such as the bowel or bladder, or has spread to other organs such as distant lymph nodes, liver, lung and bones.

The lower the stage at diagnosis, the higher the chance of successful treatment and long-term survival.

Endometrial Cancer Treatment Options

When considering your treatment plan your doctor will take into account the following factors^10,11,12:

• The stage (extent) of the cancer.
• Characteristics of the tumour (which type, subtype and grade the cancer is).
• Hormone receptor status (whether the cancer cells have oestrogen and progesterone receptors).
• Your age, overall health and any other treatments you may have for other illnesses.
• Whether you want to be able to have children.
• Your preferences.

The first goal of endometrial cancer treatment is to get rid of the cancer. Cure is likely if the cancer is detected early. For advanced cancers, the focus may be on stabilising the cancer to prevent its progression for as long as possible and improving quality of life. Endometrial cancer can be treated with the following methods, often used in combination^10,11,13:

• Surgery: Surgery is the main treatment for most endometrial cancers and consists of a hysterectomy (removal of the uterus and sometimes the cervix and upper part of the vagina), often along with a salpingo-oophorectomy (removal of both ovaries and fallopian tubes), and lymph node dissection (removal of lymph nodes). If the cancer has spread throughout the pelvis and abdomen, a debulking procedure to remove as much of the cancer as possible may be done, which can help other treatments, like radiation or chemotherapy, work better. Around 90% of women with endometrial cancer will not require further treatment after surgery⁷.

  The side effect of removing the uterus and ovaries are infertility (unable to get pregnant) and menopause. If you are premenopausal and have early-stage endometrial cancer, you may wish to discuss with your treating doctor about the possibility of having your uterus removed whilst leaving the ovaries in place to prevent menopause. You will need to weigh up the benefits of this against the higher likelihood of the cancer recurring (coming back). If you are wanting to get pregnant, it may be possible to delay surgery and try other treatments in the meantime. However, it is important to know that this is not standard treatment and may increase the chances of the cancer growing and spreading. You should discuss this in greater depth with your treating doctor and a fertility specialist in relation to your individual circumstance.

• Radiation therapy (or Radiotherapy): Radiation therapy is the use of powerful, high-energy beams to kill cancer cells or keep them from growing. It can be used either before surgery to shrink the size of the tumour or after surgery to destroy any remaining cancer cells, and may be combined with chemotherapy. External beam radiation therapy uses a machine outside the body to deliver radiation towards the cancer. Internal radiation therapy (also called brachytherapy) uses a radioactive substance contained in seeds or wires that are placed directly into the cancer tissue to release a low dose of radiation over a long period of time. For cancers that have spread to other parts of the body, such as the bones, radiation therapy can help to slow the cancer's growth and relieve symptoms such as pain. Women who are not healthy enough for surgery may receive radiation therapy as their main treatment.
• Chemotherapy: Chemotherapy is the use of drugs to kill cancer cells or stop them from dividing. It is commonly used after surgery for high grade cancers which grow and spread quickly, in advanced cancers and cancers that recur after treatment. In most cases, a combination of chemotherapy drugs is used as it tends to work better than one drug alone.
• Hormonal therapy: Hormonal therapy is a cancer treatment that counters the effects of oestrogen which may cause cancer cells to die or to grow more slowly. It is usually used to treat advanced endometrial cancer or cancer that has come back after treatment.
• Targeted therapy: Targeted therapies are drugs that block the growth of cancer by interfering with specific molecules present in cancer cells that are involved in tumour expansion and spread. Targeted therapy tends to cause less harm to normal cells than chemotherapy or radiation therapy do, due to its specific action on cancer cells. It is usually combined with chemotherapy for treating advanced endometrial cancer.
• Immunotherapy: Immunotherapy is treatment that boosts the body’s immune system to fight the cancer. This can be done by genetically engineering your own immune cells to fight endometrial cancer cells, or using medications that help your immune system cells identify and attack the cancer cells. Immunotherapy is used in the treatment of advanced endometrial cancer or cancer that has returned after initial treatment.

Endometrial Cancer Survival Rate

The overall 5-year relative survival rate across all uterine cancer cases (including endometrial cancer and rarer forms of uterine cancer) in Singapore is around 72%⁴. However, the earlier the cancer is detected and treated, the higher the likelihood for cure. The good news is that almost 70% of uterine cancers are diagnosed in Stage I, which has a 94% 5-year relative survival rate⁴.

About 25% of patients are diagnosed with advanced (Stage IV) uterine cancer and the prognosis for this group is significantly less favourable, with a survival rate of 10%⁴. It is worth noting that survival rate statistics are measured every 5 years and therefore may not reflect the recent advances in endometrial cancer treatment. People who are diagnosed with advanced endometrial cancer now are likely to have a better prognosis (outcome) than these numbers show.

It is also important to understand that these statistical numbers are obtained from a group of people with the same diagnosis to represent an average. Individuals may differ in their own experience. It is best to discuss your prognosis (outcome) with your treating doctor who would be able to provide you with more specific information based on your personal circumstances.

Endometrial Cancer Screening

Screening refers to looking for cancer before a person has any symptoms. There is currently no routine screening test recommended for endometrial cancer. The Pap test, which screens women for cervical cancer, may sometimes detect early endometrial cancers, but it is not a reliable test for this type of cancer¹⁵. It is therefore important, especially if you have one or more risk factors (see Endometrial Cancer Risk Factors above) to be vigilant and see your doctor for prompt investigation if you have any symptoms.

Women who have (or may have) hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome have up to a 70% risk of developing endometrial cancer and should therefore be monitored closely¹⁵. Yearly testing for endometrial cancer with endometrial biopsy starting at age 35 may be recommended. They may also wish to consider a hysterectomy once they are done having children¹⁵.

Endometrial Cancer Prevention

While there is no guaranteed way to prevent endometrial cancer, there are some measures you can take to reduce your risk^1,6,13:

• Stay active and exercise regularly: Exercise improves your overall health and wellbeing. Studies have also shown that women who exercise more have a lower risk of endometrial cancer⁶. Try to exercise most days of the week. If you are new to exercise, start slow with a gentle activity such as a walk around the park, and work your way up gradually.
• Maintain a healthy body weight: Keeping to a healthy weight can help reduce your risk for many conditions, including endometrial cancer.
• Eat a healthy, balanced diet: A diet with less fat, sugar, red meat and highly-processed foods, and more fresh fruits, vegetables and whole grains can help to reduce the risk of many diseases and cancers including endometrial cancer.
• Weigh up the risks and benefits of hormone replacement therapy after menopause: Like any other medicine, oestrogen treatment for menopausal symptoms should be used at the lowest dose required and for the shortest time possible. A hormone therapy medicine that combines oestrogen and progestin can reduce the risk of endometrial cancer but increases the risk of breast cancer. Regular follow-up and pelvic examination are recommended whilst you remain on hormone replacement therapy. If you have any abnormal vaginal bleeding or discharge you should see a health care provider right away.
• Get treated for endometrial problems: Endometrial hyperplasia can sometimes progress to cancer (see Endometrial Risk Factors above). Whilst some cases of hyperplasia may go away without treatment, sometimes it may require hormonal treatment or surgery.
• Talk to your doctor if you have a strong family history of cancer: You may wish to see a family genetic counselling specialist to find out more about your risks for various cancers.

References