Endometrial Cancer

Abnormal vaginal bleeding is the most common sign of uterine cancer.

The endometrium is the tissue lining the inner cavity of the uterus (or womb). The uterus, a hollow organ about the size and shape of a pear, is found in a woman's pelvic region and is the organ where the fetus grows until birth. The upper part of the uterus is called the corpus; the lower, narrower part of the uterus is called the cervix. The cervix is the opening between the uterus and the vagina. The outer layer of the uterus is called the myometrium. The myometrium is thick and composed of strong muscles. These muscles contract during labor to push out the baby.

The endometrium is soft and spongy. Each month, the endometrium is sloughed and thereby changed as part of the menstrual cycle. Early in the cycle, the ovaries secrete a hormone called estrogen that causes the endometrium to thicken. In the middle of the cycle, the ovaries start secreting another hormone called progesterone. Progesterone prepares the innermost layer of the endometrium to support an embryo should conception (pregnancy) occur. If conception does not occur, the hormone levels decrease dramatically. The innermost layer of the endometrium is then shed as menstrual fluid. This leads to the cyclical nature of the menstrual cycle.

Endometrial cancer occurs when cells of the endometrium undergo a degenerative change or malignant transformation and begin to grow and multiply without the control mechanisms that normally limit their growth. As the cells grow and multiply, they form a mass called a cancer or malignant tumor. Cancer is dangerous because it overwhelms healthy cells by taking their space and the oxygen and nutrients they need to survive and function. It can also spread, or metastasize, to other organs or tissues where it can also do damage.

Not all tumors are cancerous. Benign tumors of the uterus can grow in the uterus but do not spread elsewhere in the body. Cancerous tumors are called malignant, meaning they can look very abnormal, can grow rapidly and erratically, and spread to other tissues and organs. Cancerous tumors may encroach on and invade neighboring organs or lymph nodes, or they may enter the bloodstream or lymph fluid passages and can spread to the bones or distant organs, such as the lungs. This process is called metastasis. Metastatic tumors are the most aggressive and serious complications of all cancers.

Two main types of endometrial cancers exist. Nearly all endometrial cancers are endometrial adenocarcinomas, meaning they originate from glandular (secreting) tissue. The other type of endometrial cancer, uterine sarcomas, originates in the connective tissue or muscle of the uterus. A subtype of endometrial adenocarcinomas, adenosquamous carcinoma, includes squamous cells (that is, the type of cells found on the outer surfaces such as the skin or the outermost layer of cells on the uterine cervix). Other subtypes of endometrial adenocarcinomas are papillary serous adenocarcinomas and clear cell carcinomas. Because they are much more common than uterine sarcomas, endometrial adenocarcinomas are the focus of this article.

In developed countries, uterine cancer is the most common cancer of the female genital tract. In the United States, uterine cancer is the fourth most common cancer in women. Uterine cancer occurs in women of reproductive age and older. About one-quarter of cases occur before menopause, but the disease is most often diagnosed in women in their 50s or 60s.

The exact cause of endometrial carcinoma remains unknown, although several risk factors have been identified. Possessing one of these risk factors does not mean that a woman will develop endometrial cancer but rather that her risk of developing endometrial cancer is higher than that of another woman without the risk factor. Risk factors for endometrial cancer include the following:

• Obesity: Women who are more than 50 pounds over ideal weight have a 10-times greater risk of developing endometrial cancer than women of ideal weight. Body fat contains an enzyme which converts other hormones to estrogen, and women with excess fat have a higher level of estrogen than women without excess fat. The higher level of estrogen is believed to increase the risk of endometrial cancer.
• No pregnancies: Women who have never been pregnant have a two to three times higher risk than women who have been pregnant.
• Early puberty: Women who begin their periods before 12 years of age are at an increased risk. Early puberty increases the number of years that the endometrium is exposed to estrogen.
• Late menopause: Women who go through menopause after 52 years of age are at a higher risk of developing endometrial cancer than women who go through menopause earlier in life. Like early puberty, late menopause increases the number of years that the endometrium is exposed to estrogen.
• Treatment with unopposed estrogen: The risk of developing endometrial cancer is increased by several times in women who take estrogen replacement therapy without added progesterone.
• High level of estrogen: Women who have a high level of unopposed estrogen in the body are also at an increased risk. Several different conditions, such as polycystic ovarian syndrome, can cause a woman to have a high unopposed estrogen level.
• Treatment with tamoxifen: Women who have been treated with tamoxifen, a drug used to prevent and treat breast cancer, have an increased risk of developing endometrial cancer.
• Other cancers: Cancers of the breast, ovary, and colon are linked with an increased risk of endometrial cancer.
• Family history: Women who have a close relative with endometrial cancer have an increased risk of the disease.

The use of combination oral contraceptives (birth control pills) decreases the risk of developing endometrial cancer.

• Women who use oral contraceptives at some time have half the risk of developing endometrial cancer as women who have never used oral contraceptives.
• This protection occurs in women who have used oral contraceptives for at least 12 months.
• The protection continues for at least 10 years after oral contraceptive use. The protection is most notable for women who have never been pregnant.

By far, the most common symptom of endometrial carcinoma is abnormal bleeding from the vagina.

• In women who have been through menopause, any vaginal bleeding is abnormal and should be evaluated by a doctor.
• In women who have not been through menopause or who are currently going through menopause, distinguishing normal menstrual bleeding from abnormal bleeding may be difficult. A heavier or more frequent period or bleeding between periods is sometimes linked to cancer in menstruating women. During the transient period of going through menopause, the menstrual period should become shorter and shorter and the frequency should become farther apart. Any other bleeding should be reported to a doctor.

The following symptoms are much less common and usually indicate fairly advanced cancer:

• Pelvic pain
• Mass (swelling or lump) in the pelvic area
• Weight loss which is unintentional

Women vary considerably in the amount, duration, and frequency of their menstrual periods. A woman should be aware of any bleeding that is abnormal for her. If a woman's periods become much heavier or more frequent, or if a woman is having more than slight spotting between periods, she should talk to a health-care provider. Changes in bleeding or abnormal bleeding can have many different causes. Knowing the cause of a woman's bleeding is important.

If a woman is having abnormal vaginal bleeding or other symptoms, the evaluation starts with a detailed interview. A health-care provider asks questions about the woman's symptoms, her medical history, and any current conditions, her family's medical history, her menstrual and pregnancy history, and her habits and lifestyle. This information helps the health-care provider determine the cause of the symptoms. The interview is followed by a physical examination, including a pelvic examination.

If a health-care provider suspects uterine cancer, he or she might refer the woman to a specialist in cancers of the female genital tract (gynecologic oncologist).

Lab tests

No blood or imaging studies can confirm the diagnosis of endometrial carcinoma. Lab tests may be performed after endometrial cancer is diagnosed to ensure that a woman is able to undergo treatment and also to monitor treatment progress.

• Routine blood tests: Tests of blood chemistry, liver and kidney functions, and blood cell counts are done to check a woman's overall health and her ability to tolerate surgery and other therapy.

Imaging studies

In many instances, imaging studies are not necessary but if performed may include the following:

• Vaginal (transvaginal) ultrasound: Ultrasound is a technique that uses sound waves to take a picture of the internal organs. Ultrasound is the same technique used to look at a fetus in the uterus. To perform a vaginal (transvaginal) ultrasound, a small device called a transducer is inserted into the vagina. The device emits sound waves, which bounce off the pelvic organs and transmit a picture to a video monitor. Often, the examiner moves the transducer around slightly to get a better picture. A vaginal (transvaginal) ultrasound is safe and painless.
• Hysterosonogram is similar to vaginal (transvaginal) ultrasound, but a saline (saltwater) solution is first injected into the uterus to extend the uterine walls. This procedure can improve the picture in some cases and show the uterus in greater detail.

Ultrasound often can reveal a uterine tumor, but the findings are not always conclusive. Other imaging tests may be needed and might include the following:

• A CT scan of the pelvis would be the usual choice of a follow-up imaging test. A CT scan is like an X-ray film but shows greater detail in two dimensions. PET imaging using a radioactive isotope may be done with a CT scan to further enhance the sensitivity of the test.
• An MRI of the pelvis is another choice of a follow-up imaging test. An MRI shows great detail in three dimensions.
• A chest X-ray may be needed if metastasis to the lungs is suspected.
• A bone scan may be needed if metastasis to the bones is suspected.

Diagnostic tests

Diagnostic tests that can aid in identifying endometrial cancer include the following:

• Endometrial biopsy: If cancer is suspected, a sample of the endometrium is obtained through a biopsy. A biopsy is the removal of a very tiny piece of tissue from the body. The tissue is examined under a microscope for abnormalities that suggest cancer. Usually, a gynecologist or a gynecologic oncologist performs the biopsy, and the endometrial tissue is examined by a pathologist (a doctor who specializes in diagnosing diseases in this way). The most widely used method for obtaining the endometrial tissue is to insert a thin tube into the endometrium through the cervix. A biopsy is usually performed in the doctor's office and takes just a few minutes. Often, the results of an endometrial biopsy give a definitive answer about cancer.
• Dilation and curettage: If the results of the endometrial biopsy are not conclusive, a procedure called a dilation and curettage (D&C) may be performed. In a D&C, the doctor passes a thin instrument through the dilated cervix and scrapes tissue from the endometrium. The tissue is removed and examined by a pathologist. This procedure is usually performed as outpatient surgery and requires general anesthesia or sedation. Most women have minimal discomfort after this procedure and require a short recovery time.
• Hysteroscopy: Sometimes, an endoscope is used to guide the endometrial biopsy or D&C. An endoscope is a thin tube with a tiny light and camera at the end. The tube is inserted into the uterus through the cervix. The endoscope sends pictures of the endometrium back to a video monitor. A hysteroscopy allows the doctor to view the inside of the uterus while collecting endometrial tissue samples.

Staging

Staging is a system for classifying cancers based on the extent of the disease. In general, the lower the cancer stage, the better the outlook for remission and survival. (Remission is when no evidence of cancer is found in the body.) Health-care providers cannot make recommendations for the best treatment until they know the exact stage of cancer.

In endometrial cancer, staging is based on how far the primary tumor has spread, if at all. The staging system used for endometrial cancer was developed by the International Federation of Gynecology and Obstetrics (FIGO). The staging system for endometrial cancer is a surgical staging system, meaning that staging is based on the pathologist's findings on examining organs removed during surgery. The FIGO system uses four stages.

Stage I: The tumor is limited to the corpus (upper part) of the uterus and has not spread to the surrounding lymph nodes or other organs.

• Stage IA: Tumor limited to the endometrium or less than one half the myometrium
• Stage IB: Invasion equal to or more than one half the myometrium (middle layer of the uterine wall)
• Stage II: Invasion of the cervical stroma but does not extend beyond the uterus (strong supportive connective tissue of the cervix)
• Stage IIIA: Invasion of the serosa (outermost layer of the myometrium) and/or the adnexa (the ovaries or fallopian tubes)
• Stage IIIB: Invasion of the vagina and/or parametrial involvement
• Stage IIIC1: Cancer has spread to the pelvic lymph nodes but not to distant organs
• Stage IIIC2: Cancer has spread to the paraaortic lymph nodes with or without positive pelvic lymph nodes but not to distant organs
• Stage IV: The cancer has spread to the inside (mucosa) of the bladder or the rectum (lower part of the large intestine) and/or to the inguinal lymph nodes and/or to the bones or distant organs outside the pelvis, such as the lungs.
• Stage IVA: Tumor invasion of the bladder, the bowel mucosa, or both
• Stage IVB: Metastasis to distant organs, including intra-abdominal metastasis, and/or inguinal lymph nodes

The tumor grade is also defined during the staging process. Grade indicates the aggressiveness of the cancer. Generally, low-grade tumors are less likely to metastasize or recur after treatment.

The treatment of endometrial cancer varies depending on the stage of the cancer. Staging is based on the findings from the initial surgery, which involves the removal of the entire uterus and cervix (total abdominal hysterectomy), the fallopian tubes, and the ovaries. These organs are examined to determine the extent of the cancer (operative or pathologic staging). During this operation, cells are collected from the peritoneal cavity and tested for cancer. Usually, the lymph nodes in the pelvis and surrounding areas are removed and examined for cancer. Only then is a decision made about treatment.

Surgery is the main therapy for endometrial cancer. Other options include the following therapies:

• Radiation therapy: Radiation therapy uses high-energy radiation (like X-rays) to kill cancer cells. The radiation can be given as a beam from a machine outside the body (external beam radiation) or from a tiny source placed inside the body near the cancer (brachytherapy). Radiation may be used for stages II, III, and IV, although the decision to use radiation is based on the extent of disease. Radiation therapy is usually given after surgery to kill any cancer cells remaining in the body. Radiation is also a substitute for surgery in women who cannot undergo surgery because of other medical problems. The main side effects of radiation therapy are fatigue, diarrhea, and frequency of and burning on urination as well as a local skin reaction at the site of radiation therapy.
• Chemotherapy: Chemotherapy uses potent drugs to kill cancer cells. The advantage of chemotherapy is that it can attack cancer cells anywhere in the body. The main disadvantage of chemotherapy is the side effects that may include nausea, hair loss, fatigue, anemia, increased susceptibility to infection, and damage to organs, such as the kidneys. Chemotherapy is mainly used for advanced endometrial cancer. Although chemotherapy does induce remission in some women, their cancers often return.
• Hormone therapy: Hormone therapy is the use of hormones to fight cancer cells. Hormone therapy is generally used in only advanced and metastatic endometrial cancer.

Medications

The most widely used chemotherapy drug in treating endometrial cancer is carboplatin (Paraplatin). Carboplatin is given alone or in combination with other chemotherapy drugs. Other drugs used to treat endometrial cancer are paclitaxel (Taxol), and doxorubicin (Adriamycin PFS). Targeted therapy with bevacizumab (Avastin) and or Temsirolimus ( Torisel) have also been recommended by NCCN and used “off-label” for the treatment of endometrial cancer.

The most widely used operation for the treatment of endometrial carcinoma is a total abdominal hysterectomy. Total abdominal hysterectomy is the removal of the uterus (including the cervix). The fallopian tubes and the ovaries are also removed. Often, the surgery entails the removal of the lymph nodes (lymphadenectomy) in the pelvic and paraaortic areas.

Follow-up

After therapy has been completed, the woman undergoes testing to determine how effective the treatment has been. A woman may also undergo other blood tests and imaging tests that provide clues to disease recurrence. A doctor requires a woman to be tested and examined regularly so that disease recurrence (if it happens) can be found early. The doctor will discuss a schedule for these follow-up visits with the woman and her family members.

• Maintain a healthy weight by eating a moderate, nutrition-rich diet and exercising regularly.
• Consider taking birth control pills if warranted by her situation and medical condition.
• Avoid treatment with unopposed estrogens.

Some risk factors cannot be avoided. For example, neither a previous cancer of the breast, colon, or ovaries nor a family history of these cancers can be avoided. Early puberty and late menopause are part of a person's genetic makeup and cannot be changed.

Being vigilant to catch endometrial and other genital cancers early is something that can be controlled. A woman should not be afraid or ashamed to go to her health-care provider about abnormal bleeding or other unusual symptoms involving her genital tract. Putting off seeing a health-care provider prevents early diagnosis and treatment that, in turn, could prevent serious complications or even death.

As in all cancers, the stage of the disease is the most important factor in determining a person's outlook (prognosis). Generally, the lower the stage (that is, the more local the cancer), the better the outlook. The pathologist's findings also affect the prognosis. After a woman's staging surgery, her doctor will discuss the specifics of the cancer with her. Fortunately, most women who have endometrial cancer are cured.

Living with cancer presents many new challenges, both for the woman diagnosed with cancer and for her family and friends.

A woman will probably have many worries about how endometrial cancer will affect her and her ability to live a normal life (for example, to care for her family and home, to hold her job, to continue the friendships and activities she enjoys, and to sustain a loving relationship with her spouse or sexual partner).

Many people feel anxious and depressed. Some people feel angry and resentful, others feel helpless and defeated. For most people with cancer, talking about their feelings and concerns helps.

A woman's friends and family members can be very supportive, although they may be hesitant to offer support until they see how she is coping. If a woman wants to talk about her concerns, she should feel free to bring them up to her friends and family members.

Some people do not want to burden their loved ones, or they prefer talking about their concerns with a more neutral professional. A social worker, counselor, or member of the clergy can be helpful if a woman wants to discuss her feelings and concerns about having endometrial cancer. A woman's gynecologist or oncologist should also be able to provide a recommendation.

Many people with cancer are helped profoundly by talking to other people who have cancer. Sharing the concerns with others who have been through the same thing can be remarkably reassuring. Support groups for people with cancer (and for their loved ones) may be available through the medical center where treatment is received. The American Cancer Society also has information about local support groups.