Cervical Cancer

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Cervical Cancer

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WHAT IS CERVICAL CANCER?

The Cervix

The cervix is the lower third portion of the uterus (womb). It serves as a neck to connect the uterus to the vagina. The opening of the cervix, called the os, remains small and narrow, except during labor when it widens to allow the fetus to pass from the uterus into the vagina.

When cervical cancer develops it occurs in the thin layer of cells, known as the epithelium, that covers the cervix. Cells found in the cervical epithelial tissue have different shapes:

Squamous cells (flat and scaly). Most cervical cancer arises from changes in the squamous cells of the epithelium ( squamous cell carcinoma ).
Columnar cells (column-like). These cells line the cervical glands and cancers here are known as adenocarcinomas.
In rare cases, cancer can occur in cells that form the supportive tissue around the cervix (the stroma).

Cervical cancer usually begins slowly with precancerous abnormalities, and even if cancer develops, it generally progresses very gradually.

Precancerous Changes in the Cervix

Dysplasia is a term that refers to a precancerous condition. In the case of cervical cancer this is characterized by squamous cells of the epithelium becoming abnormal in size and shape and beginning to multiply. Dysplastic changes seen on a PAP smear may indicate the presence of cervical intraepithelial neoplasia (CIN) because they are precancerous changes found within the epithelium. These lesions are further categorized into three levels of severity: CIN I, CIN II, and CIN III (which includes carcinoma in situ ).

Cervical Intraepithelial Neoplasia (CIN). Dysplasia may become cancerous, but progression is not inevitable. Progression to cancer is characterized by the ability of the cells to actually invade into surrounding tissues. To help determine this risk, dysplasia is subdivided into three categories: cervical intraepithelial neoplasia (CIN) I, II, and III.

With CIN I, there are mild abnormalities - that rarely develop into cervical cancer. This condition may progress if untreated but is often self-limiting, usually returning to normal without treatment.
In CIN II, the lesions often appear more aggressive under the microscope and may progress to cancer unless treated.
CIN III is the most aggressive form of dysplasia and carries the highest chance of progressing to invasive cancer if not removed. CIN III includes carcinoma in situ.

Carcinoma in Situ. Carcinoma in situ is characterized by cells that look cancerous under the microscope but have not yet invaded surrounding tissue. Since it is not frank cancer, CIS is included in the CIN III category of precursor lesions. However since CIS can progress to invasive cancer, this condition should be treated as soon as possible.

Invasive Cervical Cancer

The cells of the epithelium rest on a very thin layer called the basement membrane . Invasive cervical cancer occurs when cancer cells in the epithelium penetrate this basement membrane and invade the stroma, the underlying supportive tissue of the cervix.

In later stages, the original cancer may spread to areas surrounding the uterus and cervix, to adjacent organs such as the bladder or rectum, or to distant sites in the body via the bloodstream or the lymphatic system (lymph nodes).

WHAT CAUSES CERVICAL CANCER?

Human Papillomavirus

The human papillomavirus (HPV) has been detected in virtually all invasive cervical cancers. It is spread mainly by sex with an infected partner and is now considered to be the primary risk factor for this disease. It should be noted, however, that between 5% and 30% of all women harbor this virus, but only a minority of them develop cervical cancer, so other factors are needed to trigger the disease. [ See What are the Risk Factors for Cervical Cancer? , below. ]

How HPV Contributes to Cervical Cancer. Researchers believe that most cervical cancers develop when various aggressive genetic HPV strains activate certain oncogenes (cancer-causing genes). Oncogenes called E6 and E7 are particularly important because they interfere with certain protective proteins, such as p53 and pRb, respectively. Under normal conditions, these proteins limit cell replication. Once they are blocked, cell reproduction can run rampant, leading to tumor development and cancer.

HPV Genetic Types. More than 30 genetic variants of human papillomaviruses can be passed through sexual contact form one person to another. Their individual severity, however, varies widely according to genetic type. (Women initially infected by one type of HPV are still at risk for infection from other types.)

In women with CIN I dysplasia, the HPV viruses that are present are often types 6 and 11, which are low risk. These viruses often produce genital warts (condylomata) that rarely lead to cancer. (These warts usually affect the woman's genitals, the vagina, and vulva, rather than the cervix.)
High-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 69) are associated with moderate dysplasia (CIN II) and carcinoma in situ (CIN III). HPV type 18 and HPV 16 are particularly dangerous. Severe HPV types have also been associated with an increased risk for other cancers, including other genital and lung cancers. The high-risk viruses generally produce flat and nearly invisible growths, compared to the usually harmless warts caused by low-risk HPV viruses.

Other Sexually Transmitted Diseases

Herpesviruses.Certain herpesviruses (HSV), including HSV-6, HSV-2, HSV-7, and cytomegalovirus, have been detected in women with cervical cancer. HSV-6 is under particular suspicion as playing a role in activating the papillomavirus gene. The presence of these very common viruses, however, may simply be coincidental, and they may serve no purpose other than being bystanders.

Chlamydia Trachomatis. Studies are finding an especially strong association between the incidence of Chlamydia trachomatis, a sexually transmitted infection, and HPV. ( Chlamydia trachomatis should not be confused with Chlamydia pneumonia e, a common cause of mild pneumonia in young adults, and which is not associated with cervical cancer.)

Other Sexually Transmitted Diseases. Other sexually transmitted diseases that have been associated with cervical cancer include HIV and gonorrhea. These infections, however, also may only be markers of increased sexual activity rather and may not themselves cause cancer.

WHAT ARE THE RISK FACTORS FOR CERVICAL CANCER?

Because cervical cancer is so highly associated with the sexually transmitted human papillomavirus, it is one of the few cancers that can be almost completely prevented. And because of its slow growth and the ability to be caught early on Pap smears, it can also be caught early and cured in nearly every case. With regular Pap tests, a woman's lifetime risk of squamous-cell cervical cancer may be as low as 0.8%. An estimated 12,900 American women will be diagnosed with invasive cervical cancer in 2001. The incidence has been declining steadily over the past decades.

Specific Risk Factors for Human Papillomavirus

The human papillomavirus (HPV) is spread by sexual transmission and by direct contact with an infected partner. Between 12% and 46% of American women carry the virus and in most, the virus goes away within a year. About 10%, however, remain infected. In such women, the risk for cervical cancer appears to be highest in women infected with HPV for more than six months.

Age and Screening

Fifteen percent of women with cervical cancer develop it before the age of 30. Of concern is an increase in cancer rates in women younger than twenty. (This increase may simply be due to more women being screened and so diagnosed at an early age.) If young women with early abnormal changes do not have regular examinations, they are at high risk for carcinoma in situ by the time they are age 40 and for invasive cancer by age 50.

High Sexual Activity

Women most at risk for cervical cancer are those with a history of multiple sexual partners, sexual intercourse at an early age (17 years or younger), or both. A woman who has never been sexually active has a very low risk for developing cervical cancer. Sexual activity with multiple partners increases the likelihood of viral infections (such as human papillomavirus).

Socioeconomic and Ethnic Factors

Although the incidence of cervical cancer has declined in both Caucasian and African American women over the past decades, it is much more prevalent in African Americans, and their mortality rates are twice as high as those in Caucasian women. This difference, however, is almost certainly due to social and economic differences. A 2001 study of women in the military found no differences in mortality rates when there is equal access to the same treatments.

Hispanic American women also have more than twice the risk of Caucasian women. One study suggested that the higher rate in Hispanic women, particularly new immigrants, may be due to cultural beliefs that Pap smears are an admission of immorality.

Inherited Genetic Factors

In one analysis, between 15% and 20% of women with cervical cancer had at least one close relative with the disease. Two studies have also reported that in families with cervical cancer there have also been higher rates of other HPV-related and smoking-associated cancers. Inherited factors in such cases most likely cause changes in the immune system that make such people more susceptible to HPV or other viruses.

Smoking

A carcinogenic substance in tobacco has been detected in cervical cells of women who smoke, and studies have found that smokers are at greater risk for progression from dysplasia to invasive cervical cancer. Cigarette smokers are also deficient in folate, a B vitamin. Such deficiency plays a role in the development of dysplasia.

Other Risk Factors for HPV Infection

Douching. Women who douche on a weekly basis are more likely to contract cervical cancer than those who do not. Douching may destroy the natural antiviral agents normally present in the vagina.

Pessaries. Use of a pessary (a ring-shaped plastic device that keeps the vagina and uterus from collapsing) increases the risk of chronic inflammation and viral infection at the insertion site and therefore may increase the risk for cervical cancer.

Exposure to Chemicals

Diethylstilbestrol (DES). Diethylstilbestrol (DES), an estrogen compound, was used by pregnant women in the 1940s and 1950s. The daughters of these women face a higher risk for cervical cancer, genital tract abnormalities, and miscarriage.

Environmental Chemicals. One study has reported an increase in cervical cancer mortality in women whose jobs exposed them to harmful chemicals. Such women worked in manufacturing, personal services, farm work, and as nursing aides. More research is needed.

HOW SERIOUS IS CERVICAL CANCER?

Risk for Progression from Dysplasia to Cancer

The following are some examples of the time it takes for early stages to progress to the next stage:

Only about 1% of untreated mild cervical dysplasia (CIN I) cases progress to severe dysplasia or cancer each year.
In women with untreated moderate dysplasia (CIN II), the risk for progression is 16% by two years and 25% after five years.
Most untreated carcinomas in situ will develop into invasive cancers over a period of 10 to 12 years.

Survival Rates in Women with Cervical Cancer

Over the past 30 years, the death rate from cervical cancer has declined significantly. Between 1992 and 1996 alone it declined at a rate of 2.1% per year. About 4,600 American women are expected to die of the disease in 2000. In general, 89% of women with invasive cervical cancer survive the first year after a diagnosis and 70% survive for five years. The outlook for specific women varies depending on different factors:

In women who receive treatment when cervical cancer is still local, the cure rate is about 90%. (Universal screening could then essentially reduce the cervical cancer death rate to zero. Still, only 12% to 15% of women have routine Pap smears. As a result, only 55% of white women and 44% of African American women are diagnosed at early stages.)
If the cancer cells have spread beyond the cervix, the average five-year survival rates may drop to 50% and below depending on the extent of the invasion and the type of cancer cell.

Identifying the genetic type of any present human papillomavirus may prove to be important for determining outlook and severity of cervical cancer. For example, genetic types, HPV 18 and HPV 16, are associated with severe cases. HPV 16 has also been linked to a rare form of cervical and uterine cancers.

Consequences of Treatments

The treatments for advanced cervical cancer also add to the emotional burden in premenopausal women, because they nearly always prevent future childbearing.

WHAT ARE THE SYMPTOMS OF CERVICAL CANCER?

Most women with dysplasia or carcinoma in situ do not experience any symptoms. Screening tests, therefore, are very important. When the cancer becomes invasive, abnormal or unusual bleeding can occur. Bleeding may stop and start again between regular periods or there may be bleeding after menopause. Unexpected bleeding can also occur after intercourse or a pelvic exam. Periods sometimes last longer or are heavier than usual. Increased vaginal discharge may be noticeable as well. Pelvic pain can occur, but it is not common. None of these symptoms are exclusive to cervical cancer. Sexually transmitted diseases, for instance, can cause similar symptoms.

HOW CAN CERVICAL CANCER BE PREVENTED?

Effective preventive measures and treatment of human papillomavirus (HPV) would be the best way to prevent cervical cancer. At this time, however, the best preventive measure is to reduce the risks for becoming infected.

Use of Barrier Contraceptives

Use of barrier contraceptives (particularly male and female condoms) is associated with a reduced risk of cervical cancer, even in women already infected with human papillomavirus. HPV can exist outside the area protected by the male condom, so this method is not foolproof in preventing an initial infection. The female condom is becoming increasingly popular and may prove to be particularly effective against sexually transmitted diseases.

Some studies have reported a higher risk for cervical cancer in women taking oral contraceptives (OCs). Some experts speculate that the estrogen or progestin hormones in the Pill itself may affect immune factors and increase susceptibility to the virus. Hormone replacement therapy (HRT) in postmenopausal women, however, contains the same hormones and does not appear to increase risk. The higher risk observed in OC is most likely due to a lower rate of barrier contraception use in these women. Women who have had tubal ligation are also at higher risk for cervical cancer. Such women are also less likely to have condom-protected sex.

Vitamins

Some studies have suggested possible protective benefits against cervical cancer from certain vitamins.

High blood levels of vitamins E and C have been linked with lower rates of some cancers, including cervical cancers.
Folic acid, a B vitamin, prevents birth defects and may also lower the risk for development of dysplasia (precancerous changes) leading to cervical cancer. It is not clear how strong this association is, or why this would occur. Some evidence points to its actions in reducing levels of homocysteine, a compound associated with a higher risk of cervical cancer.

There is no definitive evidence, however, that taking vitamins can prevent any cancer. Eating healthy foods rich in such vitamins and other important nutrients is in any event the best approach for overall good health.

Experimental Measure

Vaccines against HPV. Scientists are pursuing the development of vaccines for HPV, which may, in turn, reduce the incidence of the virus and cancer that may follow. Preliminary trials of the vaccine have shown some success. A number of rare types of HPV contribute to about 10% of cervical cancers, which compounds the difficulty of vaccine development, since the vaccine must include at least 21 types to be effective. Experts would like to use vaccines to both prevent and treat cervical cancer.

Interferon. Interferons are natural immune factors that stimulate the immune system to fight virus infections. A number of interferon drugs have been developed and are being used to treat recurring HPV related lesions with some success.

WHAT TESTS ARE USED TO SCREEN AND DIAGNOSE CERVICAL CANCER?

Because cervical cancer develops so slowly, it is usually preventable if discovered in its early stages using screening tests taken during regular gynecologic examinations. In spite of this, 40% of women with an abnormal Pap smear fail to follow-up for retesting and treatment.

Pap Smear

Use of the Pap smear test (named for its originator Papanicolaou) has reduced the annual death rate from cervical cancer from 26,000 in 1941 to 4,600 in 2000.

The Procedure. The most accurate results seem to be obtained 12 to 14 days after menstruation begins. Douches and spermicidal creams may clean out abnormal cells and interfere with the results of a Pap smear. They should not be used for three days before the test. In general, douching is not recommended at all. A Pap smear is painless.

Living cells are collected by gently scraping the surface of the cervix, and sometimes the upper vagina, with a plastic spatula.
A brush (cytobrush) or spatula is then used to obtain cells from inside the cervical canal. Such cells include squamous and glandular cells and those that lie higher up in the cervical canal (known as the endocervix). A combination of the brush and spatula are optimal in obtaining sufficient samples to detect cancer when it is present.
These cells are preserved with a fixative, stained for microscopic viewing, and then analyzed under a microscope by a specialist known as a cytopathologist.

Reliability. Unfortunately, the Pap smear is not perfectly reliable. Some experts believe that the push to reduce costs has made it difficult for some laboratories to be as thorough as they should. (For this reason and because of high numbers of lawsuits for inaccurate results, some laboratories are even considering not doing Pap Smears.)

In general, about 10% of Pap smears will be abnormal, but only 0.1% of the women who have abnormal results actually have cancer. A number of benign conditions can cause such a so-called false-positive result, including natural cell changes after menopause. Still, women at any age must always follow up with their physicians if a test is positive for abnormalities.
Between 15% to 25% of Pap smear test results miss abnormal and cancerous cells (known as a false-negative result). As many as 25% of invasive cervical cancer cases escape early detection because of sampling errors . Such errors occur because the sample tissue obtained misses cancer cells that are present. In addition, even if cancer cells are present in the sample, the cytopathologist (the expert examining the cells) may need to detect as few as a dozen abnormal cells that may lie in a cluster of as many as 300,000 normal ones. Abnormal cells may also be masked by infection. It should be noted, however, that the actual risk of developing invasive cancer from false negative results is very low, only 5 women per 100,000 per year. This is partly due to the fact that a repeat PAP smear may detect dysplasia that was difficult to appreciate on the prior sample.

Current Pap Smear Screening Recommendations

General Recommendations for most Adult Women

The American Cancer Society (ACS recommends that all women should have annual Pap tests after they turn 18 or when they become sexually active (whichever comes first).

Follow-up After Abnormal Results. Any abnormal result, even a mild abnormality, requires follow-up visits and perhaps additional diagnostic procedures. This is particularly important for adolescents.

Follow-up After Normal Results. If Pap smear results are normal for three consecutive years, the following recommendations for follow-up screening depend on risk:

For low-risk women, a Pap test every three years thereafter is probably sufficient to detect the slow changes that precede cervical cancer.
Women in high-risk categories should continue to have annual Pap tests.

High risk categories include the following:

Women who have had multiple sexual partners or whose male sexual partners have had multiple partners.
Women who engaged in sexual activity at a young age.
Women whose male sexual partners have had other sexual partners with cervical cancer.
Women with current or prior HPV infection.
Women who are HIV-positive or who are immunosuppressed.
Women with a history of sexually transmitted diseases.
Smokers and substance or drug abusers.
Women who have a history of cervical dysplasia or cervical cancer or endometrial, vaginal, or vulvar cancer.
Women in lower socioeconomic groups, particularly if they have not been able to obtain regular gynecologic screening and care.

It should be noted that various public health groups have different screening recommendations and such recommendations may change as research brings new findings.

Recommendations for Screening in Specific Groups

Elderly Women. Most expert groups suggest that many women over age 65 do not need screening anymore if they have had no indication of disease for nine years or more. Some experts recommend continued screening in high-risk women (those whose were sexually active before age 18, who had multiple sexual partners or whose partner did, who smoked, or are in lower income groups). Some experts argue, however, that older women who have no history of disease and who have been screened regularly and properly probably do not need regular screening.

After a Hysterectomy. Most experts do not recommend Pap smears for women over 50 who have undergone a total hysterectomy. Women who have had a hysterectomy that preserves the cervix (called a supracervical hysterectomy) should continue with Pap screening.

Women with no History of Sexual Intercourse. Women with no previous history of sexual activity should still have Pap smears. They are at low risk for squamous cell carcinoma, but adenocarcinoma (cancer that occurs in cervical glands) can occur, although this is very uncommon.

Tests for Improving the Accuracy of the Pap Smear

A number of systems are now available that are intended to improve the accuracy of the Pap smear in detecting actual cancer cells: the Papnet, Autopap, and ThinPrep.

Papnet is used to rescreen the original smear. A computer system selects over 100 abnormal images from the sample, which are then reexamined using high-resolution video. Papnet is useful for detecting cancers when there are few malignant cells in the sample and for identifying small-cell cancer.
Autopap also uses a computerized process that selects out abnormal smears, but it is performed on the original sample, and the cells are viewed under standard microscope.
ThinPrep uses the original cervical sample, which is first rinsed in a special solution to thin the mucus and eliminate debris that can obscure the findings. The result is a clear, clean sample that may be able to accurately reveal abnormal cell. Investigators are also looking at its use to detect signs of HPV and other early abnormalities.

Comparison studies using all of these tests have reported a much higher accuracy rate in detecting cancer cells than the standard Pap smear. Unfortunately, they also may produce a high number of false-positive results. This means they can identify cells as suspicious that turn out to be normal, but which may lead to additional unnecessary and even invasive tests. These tests are also expensive. They are most likely to be cost effective if they are used only as additional back up for women who are being screened every three years. There is no data as yet to determine if these new tests actually save lives, however, compared to the use of the standard PAP smear.

HPV DNA Test

The human papilloma virus DNA (HPV DNA) test detects the presence of HPV. Most experts agree, however, that the HPV test should not replace the Pap smear as a general rule. There is a high incidence of HPV infection among young women that, in most cases, does not lead to cervical cancer. Relying only on HPV tests could lead to a large number of unnecessary and invasive tests. They are proving to be a useful add-on test, however, when Pap smear results are abnormal, but it is not clear if they indicate a progressive condition.

Tests for HPV Genetic Subtypes. More sophisticated tests called polymerase chain reaction (PCR) tests can identify HPV genetic subtypes, but they are too expensive for widespread use. Two 2000 studies indicated that elevated levels of the genetic type HPV 16 were associated with a significant risk for cervical cancer. There are no preventive measures for cervical cancer once HPV has been acquired. It is not clear, then, what the appropriate steps would be for women who have high HPV 16 levels.

Tests for Additional Markers. Investigators are also developing tests to detect certain biologic factors that will be used as markers. Such markers would indicate a higher risk for cancer if HPV is also present.

Other Screening Tests

Other screening tests are being investigated for use in combination with the Pap smear for improving accuracy. For example combinations with HPV DNA tests or cervicography may prove to be more effective for detecting CIN II and III dysplasia (potentially invasive cells) than Pap smears alone.

Cervicography. Cervicography uses a photograph of the cervical region (a cervigram), which is then highly magnified and examined. It may prove to be a useful companion to a Pap test, particularly in high-risk women. It is painless, easy to use, provides documentation of the area, and is highly sensitive to abnormal changes. (It also, however, picks up abnormalities that are not cancerous.)

Acid Test. A diluted solution of acetic acid (similar to vinegar) is applied to the cervix. When viewed through a special green lens, this solution makes abnormal cells look white, whereas normal cells appear pink. Skilled physicians may also be able to spot abnormal blood vessel patterns indicative of cancer areas on the cervix.

Fluorescence Spectroscopy. Small noninvasive probes that can be swept across the surface of the cervix to detect cancer are showing promise as an effective screening tool for cervical cancer. One probe emits a laser light. The head of the probe catches the return signals from the woman's cervical cells and compares them with a computer library of cancer cells. In one comparison test, fluorescent spectroscopy was more accurate than the Pap smear but not as effective as other screening methods.

Antibody-Based Tests. Experts are working on an antibody-based method for improving the identification of true cancerous cells in a cervical smear, which could significantly reduce the need for expensive and distressing tests in women who do not actually have cancer.

Classifying Cervical Cells

The cells viewed in a cervical smear sample are classified on a scale representing the spectrum of cell changes from normal to cancerous. Using a system called the Bethesda system, the Pap smear report states whether the specimen is adequate or not ("satisfactory," "suboptimal," or "unsatisfactory"). The smear is also characterized as either "normal" or "abnormal."

Smears showing abnormal squamous cells are divided into three categories, depending on the degree of abnormality.

Atypical squamous cells of undetermined significance (ASCUS), which are mildly abnormal cells on the surface of the cervix. Over 80% of these cells normalize, but the others do not.
Low grade squamous intraepithelial lesions (LGSIL), which are associated with human papillomavirus changes, with or without early dyplasia (CIN I). Some women with LGSIL on a PAP smear may have CIN II or III on biopsy.
High-grade squamous intraepithelial lesions (HGSIL), which are associated with moderate dysplasia and other CIN II or III On biopsy.

It should be noted that while the presence of HGSIL usually indicates CIN II or III, the lower grade ASCUS or LGSIL cells can also be found in CIN II or III. Testing for the presence or absence of HPV is proving to be helpful in determining whether women with these lower-grade cells (particularly ASCUS) should have colposcopy, a more invasive diagnostic procedure to determine if the condition is actually at a more aggressive stage.

Note: An additional, but uncommon, cell category is atypical glandular cells of undetermined significance (AGUS). AGUS suggests the possibility of adenocarcinoma and some experts recommend that the next step should be a colposcopy (rather than a repeat Pap smear).

Colposcopy and Biopsy

The Pap smear only shows the presence of abnormal cells and is useful simply as a screening test that identifies women who may have preinvasive or early cancerous changes. For a definitive diagnosis, the next step is usually colposcopy, during which the cervix is visualized under low power magnification. The surgeon takes samples of suspicious cells for biopsies. A biopsy will determine the stage of the precancerous growth or whether frankly invasive cancer is present. [ See Box, above, Classifying Cervical Cells .]

The Procedure. Colposcopy can be performed in a doctor's office without anesthesia in 10 to 15 minutes. It causes about as much discomfort as mild menstrual cramps:

First, using a speculum to keep the vagina open, the physician aims a light at the cervix.
The physician then looks through the eyepiece of a special microscope, known as a colposcope, to view the cervix. (Some colposcopies include a TV attachment that transmits the picture to a nearby monitor for easier viewing.)
A biopsy (a sampling of the tissue) is taken of the white spots, of the endocervical canal (the inner part of the cervix and uterus), and any abnormal-looking areas. This may cause cramping or pinching.

After the colposcopy, the woman may have a brownish discharge from an iron solution, known as Monsel's solution, that the physician applies to prevent bleeding. The physician usually advises sexual abstinence for one or two weeks.

Follow-Up Procedures. Women with evidence of cervical intraepithelial neoplasia (CIN) or cervical cancer require treatment. Women with biopsies that show low-grade abnormal cells (LGSIL) but whose cervix is otherwise normal are generally given follow-up colposcopies.

WHAT ARE THE SPECIFIC TREATMENTS FOR CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN)?

General Guidelines

Treatment for Cervical Intraepithelial Neoplasia. Treatment of cervical intraepithelial neoplasia (CIN) (including carcinoma in situ) depends on the type and extent of abnormal cellular changes. Some of the treatments for CIN are also used for early-stage cancer.

CIN I lesions often regress and simply require careful follow up to make certain that the Pap smear and colposcopic exam return to normal.
Women with CIN II or CIN III have a finite risk for progression to invasive cancer if these areas are not removed. Therefore, finding CIN II or III is an indication for the removal of the entire extent of the suspicious area, often by an outpatient technique known as the loop electrosurgical excision procedure (LEEP).
If extensive areas of CIN II or III can not be entirely discerned by a colposcopy or if they extend into the mucous membrane in the cervical canal, a more aggressive procedure called conization (cone biopsy) may be performed instead.

Treatment for Adenocarcinoma in Situ. Some controversy exists over the treatment of adenocarcinoma in situ. Adenocarcinomas originate in glandular cells. This cancer tends to be more aggressive than the more common squamous carcinoma in situ. Some evidence suggests that it develops in numerous sites rather than a single location. Hysterectomy is generally recommended. In women who wish to retain fertility, cone biopsies may be performed, although this procedure sometimes causes sterility and it does not always remove all adenocarcinomas.

Follow-Up. Patients treated for CIN require monitoring. Testing for human papillomavirus (HPV) may prove to be useful in determining whether repeat colposcopies may or may not be needed. One study strongly suggested that if both HPV and Pap smear tests are normal on two consecutive visits, then most likely treatment was successful. If either the HPV or Pap smear is abnormal, then it may be reasonable to consider another colposcopy.

Loop Electrosurgical Excision Procedure

Loop electrosurgical excision procedure (LEEP), also called large loop excision of the transformation zone (LLETZ), uses a high frequency electrical current for cutting away diseased tissue.

A local anesthetic is applied to the cervix, and a wire loop is inserted into the vagina.
A button-sized slice of tissue is removed from the cervix for examination.
A deeper slice is used to evaluate the endocervical canal.

The procedure requires only one office visit. Extensive and deep sections of damaged tissue can be effectively removed and very high cure rates with just one treatment are possible. When used for dysplasia, it appears to be as effective as more invasive procedures [ see below ].

Some experts feel that the only downside of LEEP is its simplicity. That is, physicians may be tempted to use it for more serious conditions best treated by conization. It also may impair the ability to detect hidden invasive cancer.

Patients should be monitored closely if the biopsies on the cervical tissue removed by LEEP show any suggestions that the cancer cells may be aggressive.

Conization

Conization is an operative procedure that removes suspicious sections of cells covering an abnormally large area, or those extending into the cervical canal. Conization is preferred over LEEP or LLETZ for lesions that are so extensive that they require a larger biopsy for their complete removal.

The surgery can be performed under general anesthesia in the operating room with either traditional surgical instruments or with lasers. Use of laser surgery has reported success rates of up 96% with infrequent complications.

With conization, the ability to become pregnant can be preserved in many (but not all) cases. In women who do become pregnant, some studies have indicated that this procedure increases the risk for low-birth weight infants, so careful prenatal care is essential. Patients electing this treatment must be certain to undergo diligent follow-up evaluations.

Cryosurgery

Cryosurgery is not usually feasible for large and extensive abnormal areas. The procedure removes abnormal, but noncancerous, tissue by freezing it. Cryosurgery can be performed in a physician's office in 15 minutes without medication.

The vagina is opened with a speculum and a probe transmits gas (either nitrous oxide or carbon dioxide), which freezes the surface of the cervix.
The gas is applied for three minutes or until ice crystals form on the targeted tissue.
After waiting three minutes, freezing can be repeated for another three minutes.

Side effects from this procedure include cramping, sometimes painful, for a few hours or days and a heavy, watery discharge for 2 to 4 weeks. The discharge can be irritating, have a bad odor, and may be blood-tinged. Symptoms that may indicate serious complications are fever and chills, heavy clotted bleeding, or extreme pain in the abdomen or back.

The patient may experience a temporary change in menstrual periods; they may be heavier or lighter or come later or earlier. Tampons, douching, bathing, swimming, and intercourse should be avoided for several weeks after cryosurgery to prevent infection.

Patients undergoing this treatment must be willing to commit to regular follow-up examinations.

All-Trans-Retinoic Acid

A molecular relative of vitamin A, known as all- trans-retinoic acid, was shown in one study to reverse mild cases of cervical dysplasia in nearly half the women who used it. For advance cases, however, it has had no effect, even in adding benefits with other cancer agents. It is still an investigational treatment for early stages.

WHAT ARE THE GENERAL GUIDELINES FOR TREATING CERVICAL CANCER?

Testing for Cervical Cancer

In contrast to CIN, cervical cancer represents true invasion of cells beyond the epithelium into surrounding tissue. Cervical cancer may be detected in a biopsy performed during colposcopy for an abnormal Pap smear, or it may be visible to the naked eye when the doctor performs a speculum exam.

If invasive cancer is detected on biopsy, additional tests are performed to determine the tumor spread. The extent of the spread determines whether the cancer is operable.

An abdominal computed tomography (CT) scan is commonly used to check for spread of the disease to lymph nodes and areas around the pelvic area.
To find out if cancer has spread to areas around the uterus, other procedures are used. X-ray images are taken of the bladder and urinary system (known as intravenous pyelography or IVP) or of the lower intestinal tract (known as a barium enema).

If these tests detect cancer in any of these surrounding sites, then further tests are used:

Cystoscopy is performed to examine and take tissue from the bladder for biopsy.
Sigmoidoscopy is used to evaluate the rectum. (Both this procedure and a cytoscopy involve the insertion of a tube with a lighting device for viewing and manipulating the internal areas.)
Magnetic resonance imaging (MRI) is a sensitive and noninvasive procedure that is occasionally useful for locating the presence of tumors in the tissues surrounding the uterus.

Of interest is a technique known as a sentinel node biopsy, which has been used in breast cancer patients to help determine if cancer has spread beyond the lymph nodes. It is now being investigated for patients with early cervical cancer and may be helpful in determining which patients require lymphadenectomy (removal of the lymph nodes) in the pelvic area:

The procedure uses an injection of a tiny amount of a blue dye, into the tumor site.
These substances then flow via the lymphatic system into the so-called sentinel node . This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.

If they do not show any signs of cancer, it is possible that the remainder of the lymph nodes will be cancer-free, and further removal of lymph nodes becomes unnecessary. More investigation is required.

General Treatment Guidelines

Once diagnosed, cervical cancer (ie, invasive disease) is classified into stages according to the extent of the abnormal cells' invasion into the lining of the cervix or its spread throughout the cervix or beyond. These classifications are used to determine treatment and outlook. [ See Table Description of Cervical Cancer Stages and Their Treatments , below. ]

It is important for patients who have been diagnosed with cervical cancer to know the normal treatments for their particular stage, so that they may compare their doctor's suggestions with these norms.

In Stage I patients, the need for more aggressive treatment is correlated with larger tumor size, any involvement of blood or lymph vessels, and deeper invasion into the supportive tissues (the stroma) around the cervix.
In later stages, a greater tumor size, older age and poor general health, and cancer involvement in the pelvic and para-aortic lymph nodes (nodes near the aorta, the major artery in the body) suggest the need for investigative or more aggressive treatments.

DESCRIPTION OF CERVICAL CANCER STAGES AND THEIR TREATMENTS

Stage 0: Cancer in situ confirmed by biopsy and confined to the first layer of cervical tissue (the epithelium). Treatment Options: Loop electrosurgical excision procedure (LEEP), laser therapy, conization, or cryotherapy.

Stage I: Invasive cancer, but tumor confined to the cervix.

In Stage IA, cancer cells are microscopic, there is minimal invasion (less than 3 mm) into the supportive tissue around the cervix (the stroma), and the horizontal extent of the tumor is less than 7mm. Treatment Options: Simple hysterectomy. Conization is an alternative that is sometimes possible for women who want to preserve fertility and who have a nonaggressive tumor that has spread less than 3 mm with no lymph or blood vessel involvement. Possibly intracavitary radiation (which are radiation implants) in women who are not surgical candidates.

In Stage IA2, there is deeper invasion (greater than 3 mm but less than 5 mm) and the horizontal extent of the tumor is less than 7 mm. Treatment Options: Radical hysterectomy with surgical lymph node removal (lymphadenectomy) is a common approach.

Five-year survival rates for Stage IA can be 95% or more.

In Stage IB1, the tumor is usually visible (not microscopic) and diameter may be up to 4 cm. Treatment Options: Radical hysterectomy with pelvic lymph node removal (lymphadenectomy). Primary radiation can be used instead of surgery in patients who are poor surgical candidates or who do not plan on being sexually active.

In Stage IB2, the tumor is more than 4 cm and considered "bulky." Treatment Options: Relapse rates after surgery are higher than in Stage 1B1. Primary treatment with concurrent radiation plus platinum-based chemotherapy is reasonable.

Five-year survival rates for Stage IB can be 80% to 90% with either radiation or surgery. Survival rates are lower if lymph nodes are involved.

Stage II: Invasive cancer that extends beyond the cervix but not does not involve the pelvic side wall.

In Stage IIA, the upper two thirds of the vagina are involved but not the parametrium (the connective tissue between the pelvic floor and upper part of the cervix). Treatment Options: Same as Stage IB1 above unless tumor is bulky. In this latter case, treatment is the same as Stage IB2.

Cure rates for Stage IIA can be as high as 75% to 80% with either radiation or radical hysterectomy. Survival rates are lower if lymph nodes are involved.

In Stage IIB the cancer has spread to the parametrium. Treatment Options: Radiation therapy with concurrent cisplatin-based chemotherapy. Five-year survival rates are about 60%.

Note: Postoperative concurrent radiation and platinum-based chemotherapy may be considered for Stages IA2 through IIA tumors if the following high risk features are found at the time of primary surgery: lymph node involvement, cancerous cells found in the margins of the tumor, and involvement of the parametrium.

Stage III: Invasive cancer with tumor extending to the lower third of the vagina (Stage IIIA) or to the side walls of the pelvis (Stage IIIB). The kidney may be affected. Treatment Options: Radiation therapy with concurrent cisplatin-based chemotherapy. Five-year survival rates are about 40%.

Stage IV: Invasive cancer with tumor spread beyond the pelvis or to the mucosal lining of the bladder or rectum. Five-year survival rates are less than 20%.

In stage IVA, the cancer involves the inner lining of the bladder or rectum. Treatment Options: Radiation therapy with concurrent cisplatin-based chemotherapy.

In stage IVB, the cancer has metastasized beyond the pelvis. Treatment Options: Platinum-based chemotherapy yields short-lived response in 20% of patients. Clinical trial participation is reasonable.

Recurrent or Persistent Cancer: Cervical cancer may recur locally in the lymph nodes near the cervix, or it may metastasize to distant sites, such as the lung or bones, or it may appear both locally and in distant locations . Treatment Options: Pelvic exenteration if cancer has spread to local areas (This is removal of the cervix, uterus, vagina, and perhaps bladder, lower colon, or rectum. It is an aggressive surgical approach that may lead to cure in a small percentage of patients with recurrent cervical cancer.) Radiotherapy is another possible option, if it is technically possible. If cancer has metastasized, platinum-based chemotherapy is reasonable. Other agents may be useful under certain circumstances.

Treatment of Pregnant Women with Cervical Cancer

Only 1% of cervical cancers occur during pregnancy or shortly afterwards. To diagnose the condition, a cervical biopsy, in which a small amount of tissue is removed for diagnosis, can be performed anytime during the pregnancy. However, a cone biopsy, which removes larger amounts of tissue, is typically delayed until after the first trimester to reduce the risk of abortion. The options may be as follows:

If the abnormality is diagnosed as dysplasia or even carcinoma in situ, treatment is sometimes delayed until a few weeks after the mother gives birth, and vaginal delivery may still be possible. The risks and benefits of this approach, however, should be discussed with the physician.
If early-stage cancer is diagnosed in the late second or third trimester, a woman may sometimes be able to delay treatment until the baby is delivered. A Cesarean section is the preferred delivery method. The cancer treatment of choice is started shortly afterward.
More locally advanced invasive cancer is nearly always treated, particularly if is diagnosed within the first 20 weeks of the pregnancy.

WHAT ARE THE SPECIFIC TREATMENTS FOR INVASIVE CERVICAL CANCER?

Radiation therapy and surgery are about equally effective as a single option for treating very small cervical cancers in their earliest stages, with survival rates of up to 85% to 90% in appropriate patients. Factors influencing the choice between radiation therapy and surgery in women with invasive cancer include the patient's age and health and the extent of the disease. [ See Box , Choosing between Surgery or Radiation , below. ] Although treatments for cervical cancer have several potentially severe side effects, they are usually well-tolerated. Women undergoing any of these treatments should feel free to seek support groups and counseling, which can be as important for their outlook as medical therapies.

Choosing Between Surgery or Radiation in Early -Stage Cancer

Both surgery and radiation therapy eliminate the possibility of having children in premenopausal women.

Surgery. Surgery is almost always a hysterectomy, an operation that removes the uterus and sometimes other areas in the pelvic region as well. It does not, however, typically impair sexual activity.

In general, surgery is the better choice when small cancers are confined to the cervix in women who wish to remain sexually active.

Radiation. Radiation treatments nearly always involve damage and destruction to ovarian tissue. Early menopause often occurs. Radiation also may cause vaginal scarring. Treatments are available that may reduce these problems and women should not be shy about discussing them with their physician. Radiation therapy is usually the choice under the following circumstances:

Cancers have spread beyond the cervix to the pelvis, lower vagina, and urinary tract.
When certain tumor features indicate a high risk for recurrence after surgery.

Note: Important studies now strongly suggest that when radiation is used along with chemotherapy survival rates improve patients with stages IB to IVA compared to radiation alone. The benefits are greatest in stages I and II. There have been reports of severe late complications after treatment with concurrent radiation and chemotherapy treatments that were performed between 1983 and 1990. The agents used, however, were not cisplatin, the primary chemotherapy agent used in current combination treatment. Long-term studies are needed to determine its effects.

Surgery

In the early stages of cervical cancer, surgery is often the preferred primary treatment approach since it preserves normal sexual function. Surgery for invasive cancer is nearly always hysterectomy. Some patients desiring fertility who have early Stage I cancer may be candidates for cervical cone biopsy. [ See What are the General Guidelines for Treating Cervical Cancer? , above. ]

Hysterectomy. A hysterectomy attempts to eliminate the cancerous tissue by removing the uterus. There are several variations of this operation, depending on the location of the tumor. In women of childbearing age, the ovaries can usually be left intact. Although a woman who has a hysterectomy but retains her ovaries cannot bear children, she will not go into premature menopause. (Studies indicate that leaving the ovaries intact is safe for most women and does not pose any greater risk for cervical cancer recurrence.)

A simple hysterectomy involves the removal of the uterus and the cervix, but leaves the parametrium (tissue surrounding the uterus) and vagina intact. Lymph nodes in the pelvis are not usually removed.
A radical hysterectomy removes not only the uterus and the cervix but also the parametrium, the supporting ligaments, the upper vagina, and some or all of the local lymph nodes (a procedure called lymphadenectomy).
If the cancerous tumor recurs within the pelvis after primary treatment, a more extreme procedure may be performed called a pelvic exenteration, which combines radical hysterectomy with removal of the bladder and rectum. (In such cases, plastic surgery may be needed afterward to recreate an artificial vagina.) Patients undergoing this procedure are physically and psychologically screened in advance to determine whether it is an appropriate choice. The success rate for pelvic exenteration in halting the progression of the disease is approximately 25% to 45%.

Any form of hysterectomy is major surgery and requires at least a three to five day hospital stay. Although hysterectomy typically uses a wide abdominal incision, less invasive techniques that allow shorter recovery time may be possible for some women with early stage cancers if performed by experienced surgeons.

Side effects include difficulty emptying the bladder or bowels and a painful lower abdomen. Urinary tract infections are very common. Complications include fistulas (abnormal channels within the pelvis, which in this case are a result of surgery), bladder dysfunctions, and cysts.

Normal activity, including intercourse, can be resumed in about four to eight weeks. Once the uterus is removed, menstruation will cease. If the ovaries are removed, the symptoms of menopause will begin. These symptoms are likely to be more severe in surgical menopause than in the course of a natural passage to menopause. Hormone replacement therapy should be considered. [For more information on hysterectomy see the Report #73, Fibroids: Uterine or Report #74, Endometriosis.]

Trachelectomy. An experimental procedure called trachelectomy is being investigated for preserving fertility in certain women with early stage cancer, but it is highly controversial and appropriate in only about 5% of cervical cancer patients. In the procedure, only the cancerous portion of the cervix is removed, while the uterus and the rest of the cervix are left intact. The cervix is closed with a suture.

Small, early studies suggest it may be effective for early Stage 1 patients with no risk factors for aggressive cancer. In two small 1999 and 2000 studies, conception rates were between 27% and 37%, and survival rates after two years were over 95%. The procedure is primarily performed outside the US, and few American surgeons are skilled in this surgery at this time. Throughout the world, in fact, only about 300 of these procedures have been performed as of mid 2001. It is not foolproof. Miscarriage rates are high because the cervix is weakened, and conception rates are still lower than normal. Larger and longer-term studies are needed to confirm its long-term safety.

Radiation

Radiation therapy is a standard treatment for invasive cervical cancer. It employs high-energy rays aimed at the body from an outside machine ( external beam radiation ) and radioactive materials placed inside the body against the cervix ( intracavitary radiation ).

External beam radiation is given first and aimed at the lymph nodes along the pelvic wall. It usually involves a short period of direct-radiation five days a week for about six weeks in an outpatient setting.
Intracavitary radiation (also called brachytherapy) follows and is designed to deliver high doses of radiation to the local tumor area. Radioactive material, typically cesium-137, is encapsulated in both gold and platinum. These capsules are inserted in a long stainless steel tube, called a tandem, which is inserted in the uterus and in small stainless steel cylinders, called colpostats, which are placed against the cervix as close to the cancerous cells as possible. Commonly, two or more radiation treatments are administered for about 35 hours each time. Radiation implants may also be inserted directly into the tumor using a needle.
Thermoradiotherapy. Radiation therapy used in conjunction with hyperthermia (use of high heat often provided by ultrasound) may turn out to be a powerful combination for destroying cancer cells, but this is experimental.

In order to be effective, radiation therapy must be powerful enough to destroy the cancer cells' capacity to grow and divide. This means that normal cells are also affected, which may cause significant side effects. Fortunately, healthy cells usually recover quickly from the damage, whereas abnormal cells do not.

Side Effects. Side effects of radiation therapy include fatigue, redness or dryness in the treated area, diarrhea, frequent or uncomfortable urination, and vaginal dryness, itching, or burning. After treatment, side effects usually disappear.

Long-Term Complications. Complications include proctitis (inflammation of the rectum) and cystitis (inflammation of the bladder). Radiation therapy may also cause vaginal scarring, sexual difficulties, and premature menopause in younger women. Occasionally an abnormal tunnel between the bladder and the vagina, known as a vesicovaginal fistula, will develop and may require surgery. Temporary silicone implants that protect the small intestine during radiation therapy are being investigated and may eventually help reduce complications. Radiation itself may increase the risk for later development of cancer in the area surrounding the treated tissue.

Chemotherapy

Chemotherapy employs cell-killing drugs, known as cytotoxic agents, to destroy widespread cancer cells that have spread from their point of origin (the primary tumor) and are, therefore, no longer treatable by surgery or radiation.

Platinum-based chemotherapy agents (usually cisplatin) are now being used in combination with radiation therapy to improve survival rates in some women. Chemotherapy is being investigated in some patients with stages IB2 through IIIB to reduce tumors to the point where the cancer may be operable. Chemotherapy is also used when cancer has spread (metastasized), mostly to reduce symptoms such as pain. [ See Table under What are the General Guidelines for Treating Cervical Cancer? , above.]

Chemotherapy Agents Used.

Platinum-Based Agent s. One of the most active chemotherapeutic agents for cervical cancer is cisplatin, which enhances the effectiveness of radiation in the treatment of patients with more advanced disease stages. Cisplatin and carboplatin are known as platinum-based drugs In general, platinum-based agents are the standard drugs used for this disease. Even in treating metastatic disease, cisplatin used alone has been more helpful than even combinations of agents. There is some evidence that a combination of platinum plus paclitaxel may be more effective than platinum alone in the treatment of metastatic disease.
Other Agents. Responses, mostly in drug combinations, have also been reported with epirubicin, irinotecan, paclitaxel, bleomycin, mitomycin, vinorelbine, gemcitabine, and doxifluridine. Some drugs being investigated appear to increase tumor response to radiation therapy, and so are known as radiation sensitizers or enhancers. Topotecan, a radioenhancer, for example, is showing some promise in early studies, although toxicity is high.

For cancer that has spread to other areas from its original source (metastatic disease), chemotherapy regimens may use single cytotoxic agents or several agents in combination.

Administration. Cytotoxic agents may be given orally or as injections. Treatment may be administered at a medical center, physician's office, or even a patient's home. Some patients receiving chemotherapy may need to remain in the hospital for several days so the effects of the drugs can be monitored. The drugs are often administered in cycles with a period of rest following a period of treatment in order to allow a recovery from the side effects.

Side Effects. Chemotherapy affects all fast-growing cells, including healthy ones, so some side effects are inevitable. Fast-growing cells include those that form blood, hair, and the lining of the digestive tract. Chemotherapy that affects these cells can cause temporary lowered resistance to infection, irregular menstruation, hair loss, and nausea or vomiting. A number of treatments are available to help reduce the effects of some of these side effects. As with radiation therapy and surgery, chemotherapy may damage the ovaries and cause infertility.

Investigative Vaccines

Vaccines directed against HPV-16 and 18, the dangerous genetic variants of human papillomavirus, are under investigation. It is hoped that such vaccines would boost an immune response against the tumors.

WHERE ELSE CAN INFORMATION ABOUT CERVICAL CANCER BE OBTAINED?

National Cancer Institute.

The NCI has help line open during working hours (call 800-4-CANCER) or (800-422-6237) or on the Internet (http://cis.nci.nih.gov/). The NCI offers free information on all aspects of cancer. The following site lists clinical trials (http://cis.nci.nih.gov/resources/clinical.html)

American Cancer Society, 1599 Clifton Road, NE, Atlanta, GA 30329. Call (800-ACS-2345) or (404-320-3333) or on the Internet (http://www.cancer.org ) and (http://www.ca-journal.org )

National Women's Health Network, 514 10th St. NW, Suite 400, Washington, DC 20004. Call (202-347-1140)

Membership is $25 per year and provides a bimonthly newsletter and access to information on women's health. Reports cost $6.00 for members and $8.00 for nonmembers.

The American Social Health Association (ASHA) National HPV and Cervical Cancer Prevention Center, PO Box 13827, Research Triangle Park, NC 27709. Call (919-361-8400) or on the Internet (http://www.ashastd.org/ ). The organization provides up-to-date practical information, publishes a newsletter, and coordinates self-help groups across the country.

Internet sites for delivering personalized information on specific cancers: http://www.cancerfacts.com/

http://www.oncli.com (ask-a-physician fee-based service)

National Cervical Cancer Coalition Website (http://www.nccc-online.org/ )