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CANCER OF THE UTERUS
The uterus is the pelvic organ that holds a pregnancy and that bleeds each menstrual period. The cervix is that part of the uterus fixed at the top of the vagina. A normal uterus is about the size of a lemon. It is divided into three parts and composed of smooth muscle that forms a thick uterine wall. The inside is lined with a glandular epithelium supported by the endometrial stroma. Together, the glandular lining and the endometrial stroma are referred to as the endometrium of the uterus. The endometrium is hormonally sensitive and it changes throughout the menstrual cycle and during pregnancy.
Types of Uterine Cancers
Each of the three parts gives rise to cancers. The smooth muscle cancers are called leiomyosarcomas. There is also a benign tumor of smooth muscle called a leiomyoma. The common name for this benign tumor is myoma or fibroid. The endometrial stroma gives rise to a variety of cancers classified as sarcomas. The glandular lining gives rise to adenocarcinomas. Ninety-five percent of uterine cancers are adenocarcinomas arising from the lining. The term uterine cancer usually refers to these adenocarcinomas.
Adenocarcinomas are graded. Grade I means well differentiated--they are easily identified as originating from the glandular tissue and have easily identifiable glandular structures. Grade II cancers are intermediate in appearance. Grade III means poorly differentiated with loss of the glandular structures. They are just solid cancer. Grade I cancers are expected to behave the best and Grade III cancers, the worst.
Premalignant changes can occur in the lining of the uterus. These changes are almost always due to excessive stimulation of the endometrial glands by an excess of estrogen or prolonged estrogen influence. They can occur in younger women who do not ovulate regularly as well as in older women who are obese. Premalignant changes are called endometrial hyperplasias and are usually diagnosed by endometrial biopsy. These are not cancers and are often best treated by medication, or in some cases hysterectomy. They can also be treated with high-dose progesterone therapy. If they occur in a young woman, she will probably be infertile due to irregular or infrequent ovulation. In these cases, the treatment is with drugs that cause ovulation. If you ovulate, you will no longer have unopposed estrogen stimulation because you now have the progesterone phase to the menstrual cycle. If you get pregnant, then that will reverse the hyperplasia, as well.
Papillary serous adenocarcinomas and clear cell adenocarcinomas are subtypes of uterine adenocarcinomas. They are different because of their increased potential to spread throughout the abdomen. In this, they sometimes behave like ovarian cancer. Diagnosis and staging is the same as for the more usual endometrial cancer. The best treatment has yet to be demonstrated. There is good reason to consider treating the entire abdomen, but there is no good way to do it. Whole abdominal radiation can be done, but it can have a lot of side effects.
Risk Factors for Uterine Adenocarcinoma
Age is the most important risk factor for uterine adenocarcinoma. This cancer occurs in postmenopausal and premenopausal women. There is also a well-recognized association with estrogen. Estrogen is a hormone produced by the ovary. The ovary does several things under the direction of the pituitary gland in the head. First, the pituitary directs the ovary to start maturing an egg. It does this by sending the ovary the pituitary hormone Follicle Stimulating Hormone. The ovary develops a small cyst or follicle about one half inch in size within which the egg is kept. During the maturation process, the ovary makes estrogen. One of the effects of the estrogen produced is to stimulate the endometrial glands to grow and proliferate. Then, the pituitary tells the ovary to ovulate, which means that the ovary breaks the follicle and releases the egg. The pituitary hormone for this is called Luteinizing Hormone. The egg is ejected and floats into the fallopian tube. Under the influence of LH, the remnant of the follicle starts to make progesterone. Progesterone converts the lining of the uterus to accept the pregnancy. If pregnancy does not occur that cycle, then the ovary stops making progesterone. When the progesterone level falls, the support for the uterine lining is lost, and it falls off. This is the menstrual period. Then, it all starts over again: estrogen, ovulation, progesterone, and the period.
If the woman has a problem that prevents ovulation, then the ovary will continue to make estrogen. This will result in prolonged unopposed estrogen stimulation to the endometrial glands and will increase the risk for cancer of these glands. Postmenopausal women who are taking estrogen also will have unopposed estrogen stimulation to the uterine glands and be at increased risk for developing an adenocarcinoma of the uterus. This is why a progestin such as Provera is also prescribed. Postmenopausal women who are obese have increased levels of estrogen because adipose tissue converts other normal body chemicals into estrogen. So, they are also at increased risk. Women who take Tamoxifen for breast cancer are also thought to be at increased risk because Tamoxifen is an estrogen. These increased risks are on the order of about 5 to 12 times the normal risk.
Conditions that increase the progesterone influence on the uterus decrease the risk for adenocarcinoma of the endometrium. Pregnancy is a time of increased progesterone levels, so women who have been pregnant most of their lives are at decreased risk. Women who have taken birth control pills for a long time are at decreased risk. Birth control pills contain both an estrogen and a progestin, but the net effect is that of the progestin. Prolonged progestin influence on the endometrium produces a thinning and atrophy of the glands that is just the opposite of the effects of estrogen. There are other minor risk factors but almost all are mediated through an estrogen-progestin link.
Symptoms of Uterine Cancer
The most frequent symptom of cancer of the uterus is abnormal bleeding. In postmenopausal women, any bleeding is considered cancer of the uterus until proven otherwise. The only way to prove whether or not there is a cancer inside the uterus is by removing some of the uterine lining as a biopsy. This can often be done easily in the office without any anesthesia, or in the operating room with an anesthetic. The procedure is called a D and C, dilatation of the cervix and curettage of the uterine lining. Sometimes a scope is inserted through the cervix into the uterus so the lining can be seen and biopsied directly. This is called hysteroscopy.
Whatever the procedure, you must be convinced that the bleeding is not due to a cancer inside the uterus. The Pap test cannot assess the inside of the uterus and is of no value. A trial of hormones is inappropriate. Any postmenopausal bleeding must be taken seriously and evaluated. Occasionally a sonogram or ultrasound test that assesses the thickness of the endometrial lining can be helpful, especially in an elderly debilitated woman who cannot be easily biopsied and who is an anesthetic risk. If the lining can be seen and measures less than 5mm, then cancer is unlikely.
The problem with postmenopausal hormone replacement is that it often causes some irregular bleeding that may require a biopsy. If the hormones are taken on a cyclic basis, where there are several days each month when bleeding may occur, and if the bleeding is light and occurs on those days, then a biopsy is not necessary. If it occurs at any other time in the cycle, then a biopsy should be done. If the hormones are both being taken on a continuous basis each day and bleeding occurs, then a biopsy should be performed, especially if bleeding is persistent.
Screening for Uterine Cancer
There are no recommendations for screening for cancers of the uterus. The only screening procedure is an endometrial biopsy. Some have suggested that women who are taking replacement estrogen only, without the progesterone, should have an annual biopsy. Also, women on Tamoxifen should probably be biopsied annually. The Pap test is inadequate for cancers inside the uterus, although occasionally this cancer will be found on a Pap test. If the Pap test shows endometrial cells, then this is abnormal and should be evaluated with an endometrial biopsy.
Diagnosis
Cancers of the uterus are diagnosed by endometrial biopsy, D and C, hysteroscopy, and sometimes only after hysterectomy. The important point is that any postmenopausal bleeding must be considered a cancer of the uterus until proven otherwise. It is fortunate that uterine cancers bleed early so symptoms are often detected early. Diagnosis of uterine cancer can, thus, be made early if bleeding is not ignored. Three-fourths of all uterine cancers are diagnosed at an early stage. Of these, about three-fourths are of favorable grade. This is why the number of deaths from uterine cancer is low even though it is the most frequently diagnosed gynecologic cancer.
Staging of Uterine Cancer
Cancers of the uterus are staged by surgical exploration with removal of the uterus, tubes, and ovaries. In addition, an assessment of the pelvic and aortic lymph nodes is done.
Surgical Stages of Cancer of the Uterus
- Stage I = Cancer limited to the lining of the uterus
- Stage IA = No invasion into the uterine wall
- Stage IB = Invasion into less than one half of the uterine wall
- Stage IC = Invasion into more than one half the uterine wall
- Stage II = Extends into the cervix
- Stage IIA = Extends only superficially along the endocervix
- Stage IIB = Extends deep into the cervix
- Stage III = Cancer has spread beyond the uterus
- Stage IIIA = Cancer involves the tubes or ovaries
- Stage IIIB = Spread to the vagina
- Stage IIIC = Spread to the pelvic or aortic lymph nodes
- Stage IV = Distant metastases
- Stage IVA = Is inside the bladder or rectum
- Stage IVB = Throughout the abdomen or other distant sites
In addition, these cancers are also graded: I, II, and III. To determine the correct stage, the uterus, tubes, and ovaries will have to be removed. Sampling the pelvic and aortic lymph nodes is necessary, as well. An early stage is assigned by excluding the more advanced stage. Some cases that are obviously in an advanced stage by physical examination will not benefit from surgery and will be treated without operative staging.
Treatment
Treatment of uterine cancers is usually by a combination of surgery and sometimes radiation. Patients who are in an early stage will first have surgical removal of the uterus, tubes, and ovaries to confirm the stage. If there is only limited invasion into the wall of the uterus, and the grade is good, i.e., grade I or II, then the surgery should be sufficient and no radiation recommended. If the cancer is of a higher stage and grade, then radiation to the pelvis will often be advised. Advanced stages are treated by radiation, if possible, or by chemotherapy. Fortunately, progesterone, which has few side effects, is a good chemotherapeutic. Other types of chemotherapy have limited effectiveness, but are often used and can give an initially good response.
Most patients will be in an early stage when diagnosed, and there will be several options for treatment. Often these are elderly women who may have other medical problems. Nevertheless, a maximum effort should be taken to bring these patients to surgery, since the cure rate drops by 20% if a hysterectomy is not performed. In no other gynecologic cancer is treatment so individualized as in early stage endometrial cancer.
Prognosis
Since most patients are diagnosed at an early stage and with an optimal grade, most patients are cured. Nevertheless, stage-for-stage it is just as bad a cancer as any other. Most recurrences will occur in the first 2 years. If none have occurred by 5 years, then the patient is considered cured.
Five Year Survival for Uterine Adenocarcinoma
- Stage I = 80%
- Stage II = 65%
- Stage III = 30%
- Stage IV = 10%
Stage IA, grade I, cancers have a 5-year survival in excess of 95%. The prognosis depends on the sub-stage and grade.
Odds and Ends
Adenocarcinomas of the endometrium are often hormonally sensitive cancers. Occasionally estrogen and progesterone receptors will be determined.
There are several different cell types included in the designation adenocarcinoma. Some tend to behave in a more virulent manner but all are treated about the same.
The CA-125 blood test is often elevated in endometrial adenocarcinomas, and if so, can serve as a tumor marker.
Endometriosis is a benign condition in which endometrial tissue (glands and stroma) is misplaced onto other structures. There are often implants on the surface of the outside of the uterus or on the lining of the pelvis. They can even occur inside the ovary. Each time the lining of the uterus bleeds during menses, these implants also bleed and can cause pain and adhesions. If inside the ovary, the implants can cause a blood filled ovarian cyst called an endometrioma. Although endometriosis is a benign condition, it can cause a lot of problems. Very rarely an endometrial adenocarcinoma arises in an endometrial implant.
Uterine Sarcomas
Uterine sarcomas are rare cancers that are not easy to generalize. There are several types, each with several gradations from low-grade to high-grade malignancies. There is no standard treatment. Each case must be managed separately.
The thick muscular wall of the uterus gives rise to the benign leiomyoma and the malignant leiomyosarcoma. The benign leiomyoma is also called a fibroid tumor. They are common and often require no treatment. They are often diagnosed by physical examination when the examiner feels an enlarged lumpy, bumpy uterus. Although it is only a guess that they are fibroids, it is usually a very good guess. An ultrasound test can also indicate a possible fibroid. Fibroids can become very large and should be removed. Often there are multiple fibroids. These can be removed and the uterus preserved. Fibroids should diminish in size after menopause. Any enlarging uterus in a postmenopausal woman not known previously to have fibroids should be removed because it could be a leiomyosarcoma. If there is no need for future pregnancies, then the whole uterus should be removed.
Leiomyosarcomas are graded by the number of cells undergoing cell division. If few dividing cells are noted, then it may be a low-grade cancer or not a cancer at all. If a high number is noted, i.e., a high mitotic count, then this will be a very aggressive cancer. Even stage I leiomyosarcomas, if of a high grade, will be very aggressive and most will recur. Unfortunately, there is no convincing scientific proof that either radiation or chemotherapy can prevent a recurrence from happening.
The endometrial stroma gives rise to a variety of sarcomas, some low grade and some very high grade. There are even benign conditions that can metastasize through the veins. There is no way to generalize about uterine sarcomas. Each specific type and its grade will have to be individually considered.
Thomas G. Stovall, M.D.
Dr. Stovall is a Clinical Professor of Obstetrics and Gynecology at the University of Tennessee Health Science Center in Memphis, Tennessee and Partner of Women's Health Specialists, Inc.
Date Published: 2004-03-10
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