A mature woman’s uterus is about the size and shape of a pear and has two parts, the mainly muscular body (corpus) and the more fibrous cervix. A thick layer of muscle tissue, the myometrium, makes up most of the body of the uterus. The muscle is covered by peritoneum, which is called the serosa. It is lined by a glandular membrane called the endometrium.
In the first half of the menstrual cycle, the proliferative phase, the endometrium is stimulated to proliferate by the female sex hormone oestrogen, which is produced by the ovaries. Ovulation then occurs and, in the secretory phase of the cycle, the ovary begins to produce another hormone called progesterone. The progesterone normally “ripens” the endometrium, so that it is ready to receive a fertilised egg. If conception and implantation do not occur, the endometrium is shed in the process of menstruation.
Over 95% of cancers of the body of the uterus arise from the glands of the endometrium and are called endometrial adenocarcinomas. They are the most common gynaecological cancer in Australia, with about 2300 new cases diagnosed each year. It is the fourth most common cancer in women after breast, bowel and lung cancer. Approximately 2.7 percent of women will be diagnosed with endometrial cancer at some point during their lifetime. The disease predominantly affects obese, postmenopausal women.
Image: © 2009 Terese Winslow, U.S. Govt. has certain rights
Less than 5% of cancers of the body of the uterus arise from the connective tissue or muscle. These are called sarcomas. They include sarcomas arising from the endometrial connective tissue, endometrial stromal sarcomas and undifferentiated uterine sarcomas and sarcomas arising from the uterine muscle, called leiomyosarcomas.
Benign tumours of the uterine muscle are very common and are called fibroids or leiomyomas. After the menopause, most fibroids get smaller and cause no problems. In a premenopausal woman, both benign and malignant muscle tumours may cause heavy menstruation and an enlarged uterus. A rapidly enlarging fibroid, particularly in a postmenopausal woman, is always suspicious for a leiomyosarcoma, but her diagnosis will remain in doubt until her tumour can be examined under the microscope. This will necessitate removing her tumour only (myomectomy) or her entire uterus (hysterectomy), because it is not usually possible to sample a muscle tumour by uterine curettage.
Uterine sarcomas are cancers of the muscle or fibrous (connective) tissue of the uterus. They are very uncommon, accounting for only about 3% of uterine cancers
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.
PREVENTION OF ENDOMETRIAL 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.
SCREENING FOR 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
TYPES AND GRADES OF ENDOMETRIAL CARCINOMAS
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.
FERTILITY SPARING TREATMENT
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.
There is a need for more research into the obesity epidemic and the associated increased incidence of endometrial cancer. Most obese women have stage I cancers and have good prospects for cure of their cancer, but their obesity predisposes them to an increased rate of complications from their surgery. In addition, they are more likely to die from complications of their obesity than from their endometrial cancer.
Although most women with endometrial cancer have a very good prognosis, future research will need to focus on the less common serous and clear cell cancers and also on uterine sarcomas, to determine better approaches to earlier diagnosis and to develop better targeted therapies.
ENDOMETRIAL STROMAL TUMOURS
There are two types of endometrial stromal tumours. The more common is called an endometrial stromal sarcoma and the other is called an endometrial sarcoma or undifferentiated uterine sarcoma.
An endometrial stromal sarcoma is a relatively slow-growing cancer. A woman who has this cancer will typically be premenopausal and will report abnormal vaginal bleeding. Her diagnosis will usually be made by uterine curettage.
She will most likely be cured by hysterectomy, with or without the removal of her tubes and ovaries (bilateral salpingo-oophorectomy).
She will have about a one in three chance of recurrence of her disease in her pelvis or abdomen. Her recurrence may occur 10 to 20 years later, so her follow up should occur annually for many years. Recurrent disease usually responds well to progesterone tablets, but she may also benefit from surgical resection of her recurrent disease.
Endometrial sarcoma is a rapidly growing cancer that tends to spread via the blood stream early in its course. It is treated in the same way as an endometrial stromal sarcoma, but the chances of survival are not nearly as good.
A leiomyosarcoma is a cancer of the uterine muscle. The average age of a woman with a leiomyosarcoma is about 55 years. Her symptoms may include pelvic pain, abnormal uterine bleeding, or a lower abdominal mass. She may also feel pressure on her bladder or rectum.
She is not likely to be diagnosed before surgery, because leiomyosarcomas cannot usually be diagnosed from the results of a uterine curettage. Her heavy bleeding and enlarged uterus are likely to be diagnosed as fibroids. The only potentially curative treatment for a uterine leiomyosarcoma is hysterectomy.
Cancer cells from these tumours tend to get into the blood stream and spread (metastasise) to distant organs such as the lungs or liver fairly early and postoperative radiation or chemotherapy does not improve survival.
The overall 5-year survival for a woman with a leiomyosarcoma is about 50%. Her outlook is better if her tumour is less than 5 cm in diameter.