Cancer of the Uterus

The uterus is the pelvic organ that holds the pregnancy and that bleeds each menstrual period. The cervix is that part of the uterus fixed at the top of the vagina. The normal size of the uterus is about that of a lemon. The uterus is divided into three parts. The great bulk of the uterus is composed of smooth muscle and forms a thick uterine wall. The inside of the uterus is lined with a glandular epithelium which is 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 changes throughout the menstrual cycle and during pregnancy.

• Types of Uterine Cancers
• Risk Factors for Uterine Adenocarcinoma
• Symptoms
• Screening
• Diagnosis
• Staging
• Treatment
• Prognosis
• Odds and Ends
• Uterine Sarcomas

*terms will open new windows for definitions

Types of Uterine Cancers
Each of these three parts gives rise to cancers. The smooth muscle cancers are called leiomyosarcomas(ly o myo sarcomas). 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, that is, they are easily identified as originating from the glandular tissue and have easily identifiable glandular structures. Grade III means poorly differentiated with loss of the glandular structures. They are just solid cancer. Grade II cancers are intermediate in appearance. Grade I cancers are expected to behave the best, Grade III cancers the worst.

There are premalignant changes that 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 a prolonged estrogen influence. They can occur in younger women who do not ovulate regularly as well as in older women who are obese.

These changes are called endometrial hyperplasias. They are diagnosed usually by endometrial biopsy. They are not cancers but are often best treated by hysterectomy. They can also be treated by high dose progesterone therapy. If they occur in a young woman she will probably also be relatively infertile due to irregular or infrequent ovulation. In these cases, the treatment is by 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 also. For most women the best treatment will probably be hysterectomy.

Papillary serous adenocarcinomas and clear cell adenocarcinomas are a subtype of uterine adenocarcinomas. They are different because of their increased potential to spread throughout the abdomen. In this they sometimes behave like an ovarian cancer. The diagnosis and staging is the same as for the more usual endometrial cancer. The best treatment has yet to be demonstrated. There is a 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. This is a situation where several opinions should be obtained.

Risk Factors for Uterine Adenocarcinoma
Age is the most important risk factor. This is a cancer of postmenopausal and perimenopausal 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 (FSH). The ovary develops a small cyst or follicle about one half inch in size within which is the egg. During the maturation process the ovary is making estrogen. One of the effects of the estrogen is to stimulate the endometrial glands to grow and proliferate. Then the pituitary tells the ovary to ovulate which means break the follicle and release the egg. The pituitary hormone for this is called Luteinizing Hormone (LH).

The egg is ejected and floats into the fallopian tube. The remnant of the follicle, under the influence of LH 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 this will increase the risk for cancer of these glands. Postmenopausal women who are taking estrogen also will have an 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 an increased level of estrogen because the 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 5-12 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 which 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 not to be. The only way to prove that there is or is not 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 it can be done in the operating room with an anesthetic. The procedure is called a D&C, dilatation of the cervix and curettage of the uterine lining. Sometimes a scope can be inserted through the cervix into the uterus and the lining visualized 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 also an anesthetic risk. If the lining can be seen and measures less than 5mm, then there is unlikely to be a cancer present.

The problem with postmenopausal hormone replacement is that it often causes some irregular bleeding which 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 biopsy need not be done. 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

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&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 early and if the bleeding is not ignored, diagnosis is early. 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

In addition, these cancers are also graded; Grade I, II and III. To determine the correct stage the uterus, tubes and ovaries will have to be removed as well as sampling the pelvic and aortic lymph nodes. 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 can be treated without operative staging.

Treatment
Treatment of uterine cancers is usually by a combination of surgery and radiation. Those that are at an early stage will be operated first with 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 will be sufficient and no radiation will be recommended. If of higher stage and grade then radiation to the pelvis will often be advised. Some doctors prefer to give radiation prior to surgery but that is becoming less prevalent. Advanced stages are treated by radiation if possible, or 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. With no other gynecologic cancer is treatment so individualized as with 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 two years. If none have occurred by five years the patient is considered cured.

FIVE YEAR SURVIVAL FOR UTERINE ADENOCARCINOMA

Stage IA, grade I, cancers have a five year survival in excess of 95%. The prognosis depends on the substage and the grade.

Odds and Ends
Adenocarcinomas of the endometrium are often hormonally sensitive cancers and occasionally estrogen and progesterone receptors will be determined, but this is not commonly done.

There are several different cell types included in the designation adenocarcinoma. Some trend 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. Often there are 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 it can cause a blood filled ovarian cyst called an endometrioma. Endometriosis is a benign condition but one that can cause a lot of problems. Very rarely an endometrial adenocarcinoma can arise in an endometrial implant.
NEVER, NEVER IGNORE POSTMENOPAUSAL BLEEDING, AND DO NOT LET YOUR DOCTOR IGNORE IT EITHER. YOU MUST PROVE THAT IT IS NOT DUE TO A UTERINE CANCER.

Uterine Sarcomas
Uterine sarcomas are rare cancers and 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. It is only a guess that they are fibroids but usually a very good guess. An ultrasound test can also indicate a possible fibroid. Fibroids can become very large and then should be removed. Often there are multiple fibroids and occasionally these can be removed and the uterus preserved. Fibroids should diminish in size after the menopause. Therefore, any enlarged uterus in a postmenopausal woman not known previously to have fibroids should be removed because it could be a leiomyosarcoma. An enlarging fibroid in a premenopausal woman should also be removed. 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 are noted ,i.e. a high mitotic count, then this will be a very aggressive cancer. Even stage I leiomyosarcomas, if 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.

William M. Rich, M.D.
Clinical Professor of Obstetrics and Gynecology
University of California, San Francisco
Director of Gynecologic Oncology
University Medical Center
Fresno, California