If a woman does not ovulate, her ovaries will produce oestrogen but not progesterone, so her endometrium will be exposed to “unopposed oestrogen”. This may lead to the development of a benign condition called endometrial hyperplasia. Continuous oestrogenic stimulation of hyperplastic endometrium may eventually lead to the development of endometrial cancer.
Any circumstance which leads to continuous production of oestrogen without any production of progesterone will increase the likelihood of a woman developing endometrial hyperplasia and endometrial cancer. These circumstances include:
- infertility, when associated with lack of ovulation. Polycystic ovarian syndrome, a reasonably common diagnosis for a premenopausal woman, is associated with infertility. In this condition, a woman’s ovaries contain many cysts and produce oestrogen, but ovulation rarely occurs, so progesterone is rarely produced.
- late menopause, (55 years or beyond), because such a woman typically has cyclical bleeding without ovulation for the last few years before her menopause
- postmenopausal medication with oestrogen only for hormone replacement therapy (HRT) or tamoxifen for breast cancer
- oestrogen producing tumours, such as a granulosa cell tumour or thecoma
There has been an increase in the incidence of endometrial cancer over the past 2 decades because of the increased proportion of women who are obese. Oestrogen is produced in a woman’s fat cells, but there is no production of progesterone. The more fat cells that are present, the greater the production of oestrogen, which progressively stimulates the endometrium and may lead to hyperplasia and in some cases to cancer.
Tamoxifen functions mainly as an anti-oestrogen and is commonly used for the treatment of women with an oestrogen sensitive breast cancer. Tamoxifen also has a weak oestrogenic action. A postmenopausal woman taking Tamoxifen for 5 years will more than double her risk of developing endometrial cancer.
A woman with a mother, sister, or daughter with uterine cancer has a moderately increased risk of developing the disease herself. About 5% of women who develop endometrial cancer have an identifiable, strong hereditary predisposition to the cancer. These women have inherited genes that are responsible for the Lynch Syndrome, which is also called the hereditary nonpolyposis colon cancer syndrome (HNPCC). A woman with this syndrome has about a 40% risk of developing endometrial cancer, often before her menopause and a 40% risk of developing bowel cancer. She also has an increased risk of other cancers, including a 10% risk of developing ovarian cancer.
Use of combined (oestrogen and progestagen) oral contraceptives for at least 5 years will significantly decrease a woman’s chance of developing endometrial cancer.
Population screening, which means testing women for endometrial cancer who have no symptoms or signs, is not feasible, because there is no simple method of early stage cancer detection available, such as a blood test. Only about 50% of women with endometrial cancer will have malignant cells detected by a Pap test, so a negative test provides no reassurance about this condition. A normal pelvic examination will give even less reassurance.
Ultrasonic imaging, with the ultrasonic probe placed in the vagina (transvaginal ultrasound) can show abnormal thickening of the endometrium in early endometrial cancer, but the test is only cost-effective and acceptable as a screening test in exceptional circumstances. It is most commonly recommended to a woman with polycystic ovarian syndrome or a family history of Lynch Syndrome, to be done annually until she is ready to have a hysterectomy.
If the ultrasonic examination is abnormal, her endometrium should be sampled (endometrial biopsy) and examined under the microscope to make a definitive diagnosis. It is usually possible for a gynaecologist to sample her endometrium in the consulting rooms or clinic, using a small plastic tube that is introduced into her uterus through her cervix. No anaesthetic is required.
A woman with endometrial cancer will usually experience abnormal vaginal bleeding quite early in the course of her disease. Postmenopausal bleeding is the most common presenting symptom. This symptom always causes a woman some alarm, so she is likely to seek medical advice without delay. Fortunately, most postmenopausal bleeding is not caused by cancer, but rather by use of hormone replacement therapy (HRT), or by thinning of her vaginal skin (atrophic vaginitis), which is caused by lack of oestrogen.
Endometrial cancer is uncommon in a premenopausal woman but when it does occur, the diagnosis is often delayed. It causes bleeding between periods (intermenstrual bleeding), which is usually thought to be just due to irregular menstruation, without any serious cause or consequences. Most of the time, this will be true, as this type of bleeding is typically caused by hormonal changes and not by cancer.
As a woman approaches menopause, her menstruation should get progressively lighter and occur at longer intervals before stopping. If her bleeding is occurring more frequently or is getting heavier, it is abnormal (perimenopausal bleeding) and should be investigated with the possibility of endometrial cancer in mind.
Any woman with abnormal perimenopausal or postmenopausal bleeding should have a transvaginal ultrasound. If her endometrium is thickened, some endometrial tissue must be obtained (endometrial biopsy). If endometrial cancer is diagnosed, treatment can be arranged. If her endometrial tissue is normal or shows only hyperplasia, a hysteroscopy and uterine curettage should be performed, usually under general anaesthesia, to be certain there is no cancer present.
A hysteroscope is a small tubular metal instrument that can be passed into the uterus via the cervix to allow illuminated inspection of the endometrium. A curette is a metal instrument with a sharp loop which is used to remove a sample of tissue from the endometrial cavity to send to the pathologist.
In a premenopausal woman, interpretation of an ultrasound can be more difficult, because her endometrium continually changes thickness. Her abnormal bleeding should be investigated by thorough examination of her vulva, vagina and cervix, followed by hysteroscopy and uterine curettage if everything else looks normal.
Endometrial carcinoma is staged according to the International Federation of Gynecology and Obstetrics (FIGO). A summary of the staging is as follows:
- Stage I means the cancer is confined to the body of the uterus
- Stage II means the cancer has spread to the cervix
- Stage III means the cancer has spread to the vagina, tubes, ovaries or lymph nodes
- Stage IV means the cancer has spread to the bowel, bladder or to distant organs such as the lungs or liver
Under the microscope, about 75% of endometrial cancers have a structural appearance similar to normal endometrium. Such tumours are called endometrioid adenocarcinomas. These cancers are divided into three grades, I to 3, depending on how closely they resemble normal endometrium. If a woman’s cancer looks very similar to normal endometrium, it is grade I and she has the best chance of cure.
Other types of endometrial adenocarcinomas have a different appearance under the microscope. They include serous and clear cell carcinomas and carcinosarcomas. A woman with any of these three cancers will not respond as well to treatment as a woman with a grade I endometrioid carcinoma. Her prognosis will be more comparable to that of a woman with a grade 3 endometrioid carcinoma.
A woman’s endometrial cancer can spread by the following means:
(1) by direct growth into the underlying muscle of her uterus and eventually, if not treated, into her surrounding organs such as the cervix, vagina, bladder and rectum
(2) by shedding of cells that may migrate from her uterine cavity, through her Fallopian tubes and into her peritoneal cavity, where they may start new tumour growths on her ovaries or peritoneum
(3) via lymphatic channels, lodging in lymph nodes in her pelvis or abdomen,
(4) via her blood stream, travelling to start secondary tumour growths (metastases) in distant organs such as her lungs and liver.
The most important treatment for a woman’s endometrial cancer is surgical removal of her uterus, tubes and ovaries (hysterectomy and bilateral salpingo-oophorectomy). If she has a high risk type of cancer, e.g., a grade 3 endometrioid carcinoma, serous carcinoma, clear cell carcinoma or carcinosarcoma, her pelvic lymph nodes should also be removed (pelvic lymphadectomy). Increasingly, this operation is being done by using a laparoscope, sometimes called keyhole surgery.
If a woman has cancer discovered in her lymph nodes (lymph node metastases) or has other high-risk features, she may be offered radiation therapy, which should usually commence about 6 to 8 weeks after her operation.
Postoperative chemotherapy is not routinely given to women with endometrial cancer at the present time, but a possible role for chemotherapy is currently being addressed in international clinical trials.
Endometrial cancer occasionally occurs in a woman who is younger than 40 years of age and who would like to have more children. If her cancer is grade 1 and limited to her endometrium and/or superficial myometrium, her cancer can often be controlled effectively with hormonal therapy, using progesterone.
A young woman with endometrial cancer is likely to have polycystic ovarian syndrome. Even though hormonal therapy may allow her to delay having a hysterectomy, becoming pregnant is likely to be difficult for her and assisted reproduction, such as in vitro fertilisation (IVF) may be necessary.
After hormonal therapy, recurrence of her cancer is quite likely, so careful monitoring with transvaginal ultrasound is essential when she is not pregnant. Once her childbearing has been completed, she should be offered a hysterectomy.
Most women with endometrial cancer have a grade I or 2 endometrioid carcinoma and the outlook for these women is very good. The 5-year survival rate is about 85%.
Women with a grade 3 endometrioid, serous or clear cell carcinoma, or a carcinosarcoma have a worse outlook, because these high-risk cancers tend to spread early. The 5-year survival rate is about 50-60% for women with these less common tumours.
Follow-up consultations are usually performed every 3 months for 2 years and every 6 months for a total of 5 years. A history should be taken and any symptoms such as vaginal bleeding or discharge, persistent cough, persistent pain, abdominal swelling or weight loss should be investigated. Physical examination should be performed, including an inspection of the top of her vagina (vaginal vault). Some doctors take a cytology sample [Pap test] from the vaginal vault of any woman who has not been treated with postoperative radiation. Her vaginal vault is the most likely site for recurrence in a woman who has not received adjuvant radiation, although her risk of recurrence is very low.