CANCER OF THE CERVIX

CAUSE
SCREENING
SYMPTOMS
DIAGNOSIS
STAGING
TREATMENT
PROGNOSIS
RECURRENCES
CERVICAL CANCER DURING PREGNANCY

The cervix is the part of the uterus connected to the upper vagina. It is the structure that dilates during childbirth to allow the baby to traverse the birth canal. There are two major types of cancer that develop from the cervix. Squamous cell cancers arise from the squamous epithelium that covers the visible part of the cervix. Adenocarcinomas arise from the glandular lining of the endocervical canal. About 85% of cervical cancers are squamous cell cancers and the remainder adenocarcinomas. Each of these major types has several subtypes that may require special treatment; otherwise they are all managed similarly. Squamous cell cancers are unique because there is a well established progression through premalignant changes before a cancer develops. These premalignant changes are easy to detect by a simple screening test called the Pap test.

CAUSE

The cause of cervical cancer is unknown. There is a strong association with certain subtypes of the Human Papilloma Virus (HPV) for the squamous cell cancers. HPV can be transmitted sexually, so there is an association with sexual activity. The strongest association, however, is that women who have been celibate all their lives almost never develop a squamous cell cancer of the cervix. They are at risk, however for an adenocarcinoma of the endocervix. Infection with HPV, which also causes genital warts, is common; cervical cancer is not. HPV changes are often noted on the Pap test report and should not cause alarm. If there are any premalignant changes diagnosed then they will be treated. Treatment of these premalignant changes is usually simple and almost 100% effective.

Sixty years ago cancer of the cervix was the leading cause of cancer deaths in women in this country, surpassing even those from breast cancer. The death rate began to fall in the 1940's and has continued to fall, in spite of the sexual revolution, third world immigration and the prevalence of HPV. The reason for this large decrease is unknown. It began before Pap test screening became prevalent. Cervical cancer is still the leading cause of cancer deaths in women in many third world countries. There are about 16,000 new cases diagnosed each year in the USA, with about 5,000 deaths. There are about 180,000 new cases of breast cancer each year and about 60,000 women die of lung cancer each year.

All sexually active women are at risk for the development of cervical cancer. The risk seems to be increased with smoking and promiscuity of the woman or her male partner. This is the standard text book explanation for an increased risk. But, in my experience, it is not a likely explanation for the patients that I have treated. It is not increased by the use of birth control pills, family history or the development of genital warts. Almost all cases occur in women who have not had regular screening with Pap tests. This is one cancer that can be prevented, in most cases, by screening for the premalignant changes.

SCREENING

Screening means to test for the presence of a cancer before there are any symptoms or findings on examination. If there are symptoms or abnormal findings on examination then a diagnostic test must be done; not a screening test. The major benefit of the Pap test is to detect changes on the cervix before they become cancerous. These premalignant changes are referred to as dysplasias or as intraepithelial neoplasias. They are easily and effectively treated.

When a Pap test is reported as abnormal a well established evaluation is begun. Only after this evaluation is completed can a diagnosis be made as to the true condition of the cervix. Only after the diagnosis is established can treatment be recommended. It is a major mistake to treat on the basis of an abnormal Pap test without a diagnosis. An abnormal Pap test is not a diagnosis. It is only an abnormal screening test that must be evaluated. This evaluation is described in ALL ABOUT PAP TESTS.

SYMPTOMS

There may be no symptoms of a very early cervical cancer, but by the time it is large enough to detect visually it is usually symptomatic with abnormal bleeding. Often this abnormal bleeding occurs after sexual intercourse. Cancers must make new blood vessels as they grow. These new blood vessels are often abnormal and break easily which is why bleeding is a sign of cancer. The cancer also outgrows some of its blood supply, so portions of it are deficient in oxygen. This causes some of the cells to die and for the tissue to become infected. In the cervix this causes a watery or foul discharge that will be noticeable and resistant to most treatments for the usual vaginal infections.

As the cancer increases in size it usually grows laterally toward the pelvic wall. The tubes from the kidneys (ureters) that bring urine to the bladder pass through this area and they are easily obstructed. If that happens to both of the ureters, then this will result in renal failure, coma and death. If the cancer grows into the pelvic wall it will press on the nerves that go to the leg and cause unremitting leg pain. These are symptoms of an advanced cancer. Premalignant changes have no symptoms and are usually not noticeable on visual examination.

Cervical cancers usually do not spread early. They tend to be slow growing and cause most of their problems in the pelvis. Although distant metastases occur they are usually late events. Cervical cancers can spread by way of the lymphatic system. The lymphatic vessels drain from the cervix to clusters of lymph glands along the pelvic wall. The lymphatics follow the large blood vessels so the route of drainage is upward along the pelvic wall, then along the midline of the backbone and then to the chest. If the pelvic lymph nodes on one side of the pelvis become obstructed with cancer then that will cause swelling in the leg on that side. This is another sign of advanced cancer.

DIAGNOSIS

The diagnosis of cervical cancer is usually not difficult. It is usually big enough to be seen and can be biopsied. If it arises from up inside the cervical canal then it may not be visible. This will require that a portion of the cervix be removed for diagnosis. These large biopsies can be accomplished by either a LEEP or cone procedure. A major mistake is to rely on a Pap test to rule out a cancer in a woman who has symptoms or findings that could be due to a cancer. A normal Pap test never excludes a cancer. Cancer can only be excluded by the proper biopsies. It is known that about 10% of women with an obvious cancer of the cervix will have a Pap test that is essentially normal. This is because there is so much inflammation and dead cell debris that it masks the cancer cells. Very rarely, the cervix may be too small or inaccessible to biopsy properly. In these situations a simple hysterectomy may have to be done for diagnosis.

STAGING

Whenever a cancer is diagnosed the next step is staging. This is a determination of the extent of the cancer. For cervical cancer this is determined by physical examination, chest x-ray, kidney x-rays and looking inside the bladder and rectum. CT scans and MRI scans can be done but they are not used to assign a stage. Likewise, surgical exploration is not used to assign a clinical stage.

		CLINICAL STAGES OF CANCER OF THE CERVIX

	Stage I		Cancer confined to the cervix
		IA	Invasive cancer detectable microscopically only
		IA1	Invasion less than 3 mm and width less than 7 mm
		IA2	Invasion more than 3 mm but less than 5 mm
		IB	All others, any visible cancer
		IB1	Cervix less than 4 cm in diameter
		IB2	Cervix greater than 4 cm

	Stage II	Spread to adjacent structures
		IIA	Spread onto the vagina
		IIB	Spread laterally toward the pelvic wall

	Stage III	More extensive but still within the pelvis
		IIIA	Extends to the lower vagina
		IIIB	Extends onto the pelvic wall, obstructed ureter

	Stage IV	Distant spread or involvement of a pelvic organ
		IVA	Involves the inside of the bladder or rectum
		IVB 	Distant metastases, i.e. lung, liver or bone

TREATMENT

In general, cancers of the cervix are treated with radiation. The major exceptions are for those that are stage I and some that are stage IV. Stage IA cancers that invade less than 3mm deep can sometimes be treated by simple hysterectomy or even in special cases by cone biopsy. All other Stage I cancers are treated either by radical surgery or radical radiation. Some stage IIA cancers can also be considered for surgery. Otherwise, all stage II, III and IV cancers are treated with radiation. Occasionally ultra-radical surgery is done on some stage IVA cancers. Surgery for stage IB and some IIA cancers requires a radical hysterectomy and removal of the pelvic lymph nodes. Radical hysterectomy means that the cervix is removed by staying as far away from it and the cancer as possible. A regular or simple hysterectomy removes the cervix by staying as close to it as possible.

Cancer surgery requires that the cancer be removed with as good a margin of uninvolved tissue as can safely be taken. The radical hysterectomy technique removes all the supporting ligaments to the cervix which means that the dissection is very close to the bladder and to the rectum. The ureters have to be dissected out and the tissue around them removed. A radical hysterectomy with removal of the lymph nodes takes about 4 hours to perform. A simple hysterectomy takes only about 1-2 hours. The ovaries are not a part of the problem with cervical cancer and can be left in place. If after surgery the pathology indicates that there are positive lymph nodes or that the surgical margins are close, then pelvic irradiation with or without chemotherapy may be advised.

Ultraradical pelvic surgery for advanced or recurrent cancer means that all the pelvic organs are removed. The uterus and cervix, vagina, bladder and rectum are removed. Sometimes a vagina can be reconstructed. If the rectum can be reattached then there will be no need for a colostomy. Sometimes a continent urinary reservoir can be constructed. Otherwise a bag will have to be placed for the urine to drain through an ostomy in the abdominal wall. This ultra-radical surgery is done if there is an extensive cancer involving the bladder or rectum, but without spread beyond these structures. It is also done for cancers that recur after pelvic radiation if they are confined to the pelvis.

Radiation therapy usually requires a treatment each day, five days a week, for about five weeks. Each treatment takes only several minutes. This is called external or teletherapy. The entire pelvic area is irradiated by an x-ray beam usually generated by a linear accelerator. Everything in the pelvis is irradiated, bladder, rectum, large intestine, small intestine, bone and skin. Following this treatment, a radioactive source is placed inside the cervix and vagina and left in place several hours or several days. This is called an implant, radium implant, intracavitary implant or any of several other names. A more accurate term is brachytherapy which means slow therapy.

Often when cancer of the cervix is being treated with radiation, chemotherapy is also given to increase the effects of the radiation. Otherwise, chemotherapy is not used as initial treatment for cancer of the cervix. There are some investigational studies in which chemotherapy is given first and then either surgery or radiation performed.

Complications from treatment with surgery are related to anesthesia and injury to other organs such as the bladder and ureters. There is also the risk associated with blood transfusions and infection. These complications usually occur early and are remediable. Radiation complications can occur years later and are difficult to fix.

PROGNOSIS

Most early cancers are cured; most advanced cancers are not. If a cancer was removed surgically then it cannot come back. If it recurs that means that a cancer cell had already spread by the time the cancer was removed, and it took a couple of years to grow large enough to be detected. If a cervical cancer is destined to recur, about 85% will recur within the first two years after treatment. If there has been no recurrence by five years, then the cancer is unlikely to recur and is considered cured.

FIVE YEAR SURVIVAL RATES FOR CERVICAL CANCER

	Stage I		80%
	Stage II	65%
	Stage III	30%
	Stage IV	15%

These are somewhat misleading numbers. Certainly, almost all stage IA cancers will be cured. Stage IB cancers, if the nodes are negative and the surgical margins adequate will also almost all be cured.

RECURRENCE

If the cancer recurs then the outlook is generally poor. If initially operated then the recurrence can be treated with radiation. If initially irradiated then sometimes ultra-radical surgery can still be curative. If there is a recurrence in the cervix or vagina after the pelvis has been irradiated and there is no evidence of cancer anywhere else, then ultra-radical surgery can be done. This is called a total pelvic exenteration. The uterus, tubes, ovaries, bladder, colon and vagina are removed. Sometimes the vagina can be reconstructed and the colon reattached. A continent urinary reservoir can also be done.

Isolated recurrences elsewhere such as lung or liver can be removed surgically or irradiated if not removable. The treatment of isolated recurrences can be curative since cervical cancers do not usually spread widely throughout the body. Chemotherapy for recurrent cancer has not been very effective, but is often tried.

CERVICAL CANCER DURING PREGNANCY

When an abnormal Pap test is obtained on a woman who is pregnant the evaluation is modified. In general, the pregnancy has no effect on the cervical problem and the cervical problem has no effect on the pregnancy. However, the cervix is best not manipulated or biopsied during the first trimester because the risk a spontaneous miscarriage is about 20%. Should this happen, the biopsy will be blamed, although it will not have been the cause.

There is no urgency to diagnose a premalignant condition during pregnancy. All that is really necessary is to exclude or diagnose an invasive cancer. Often this can be accomplished by a colposcopic examination, without the need for any biopsy. The premalignant conditions can easily wait until 6 weeks after the baby is born to evaluate and treat. Sometimes however, biopsies and even cone biopsies must be done. The best time for these biopsies is the early second trimester because the risk for a spontaneous miscarriage has past and cervical manipulation during the third trimester risks premature labor.

If an invasive cancer is diagnosed during pregnancy, the treatment is the same as for those not pregnant. Except, treatment can be delayed until the baby is sufficiently mature to be delivered if the diagnosis is made after the 24th week of pregnancy. The baby will usually reach lung maturity sometime between the 32nd and 36th week.

The best plan is to stay up to date with Pap test screening and prevent the development of this cancer.

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