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In This Report

•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Prognosis
•	Symptoms
•	Prevention
•	Diagnosis
•	Treatment for CIN and Carci...
•	Treatment for Cervical Canc...
•	Treatment for Invasive Cerv...
•	Resources
•	References

Encyclopedia

•	Cervical cancer
•	Cervical dysplasia

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Cervical Cancer

Highlights

Vaccines to Prevent Cervical Cancer

• An experimental vaccine called Gardasil provides 100% protection against the most deadly types of human papilloma virus (HPV), according to study results released in 2005. Gardasil protects women against HPV 16 and 18, the HPV strains that cause 70% of all cervical cancer cases. The vaccine also prevents infection from HPV strains that cause genital warts. The FDA will likely approve the vaccine for use in June, following a key recommendation from an advisory panel.
• Another investigational cervical cancer vaccine, Cervarix, has been shown to protect against HPV 16 and 18, as well as some other types of cancer-causing human papilloma viruses. It does not, however, protect against genital warts.

Risk Factors

• Smoking can increase the risk of developing cervical cancer. Secondhand smoke may also raise the risk. According to a 2005 study, women who live with smokers are 40% more likely to develop cervical cancer than women who are not exposed to household cigarette smoke.

Talk to Your Doctor About HPV

According to a 2005 survey released by the American Association of Reproductive Health Professionals, women and their doctors are not communicating very well about cervical cancer and its risks. The survey results revealed that:

• Only 17% of women realize that cervical cancer is the most preventable type of cancer.
• Only 23% of women correctly identify HPV as the leading cause of cervical cancer.
• Nearly half of women (over age 30) have heard of HPV, but only 18% have discussed it with their doctors. Women between ages 35 and 55 have the highest risk for HPV infections and cervical cancer.
• Older women need to discuss HPV testing with their doctors. Some women over age 30 may benefit from a liquid-based Pap test combined with an HPV DNA test.

Introduction

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 childbirth when it widens to allow a baby to pass from the uterus into the vagina.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Cervical cancer develops in the thin layer of cells called the epithelium, which cover the cervix. Cells found in the this 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. Cervical cancer is the most preventable type of cancer and is very treatable in its early stages. Regular Pap tests and human papilloma virus (HPV) screening can help detect this disease early.

Precancerous Changes in the Cervix

Dysplasia. Dysplasia is a term that refers to a precancerous condition. It may become cancerous, but not always. In the case of cervical cancer, dysplasia indicates that the layer of cells that covers the cervix (squamous epithelial cells) are abnormal in size and shape and beginning to grow.

Cervical Intraepithelial Neoplasia (CIN). Dysplastic changes seen on a Pap smear may indicate the presence of cervical intraepithelial neoplasia (CIN). This means precancerous changes are found within the lining of the cervix. The changes are categorized according to severity: CIN I, CIN II, and CIN III (which includes carcinoma in situ).

• With CIN I, there are mild abnormalities that rarely develop into cervical cancer. This condition may progress if untreated but often goes away without treatment.
• In CIN II, the lesions often appear more aggressive under the microscope and may turn into  cancer unless treated.
• CIN III is the most aggressive form of dysplasia. If not removed, there is a high chance that it will turn into invasive cancer. CIN III includes carcinoma in situ (CIS). CIS is an early stage of non-invasive cancer -- the cells are confined within the tissue where they grew and have not yet invaded surrounding tissue. 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.

Click the icon to see an image of cervical dysplasia.

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 cross this 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 near by organs such as the bladder or rectum, or to distant sites in the body by way of the bloodstream or the lymph nodes.

Causes

The human papillomavirus (HPV) has been detected in virtually all invasive cervical cancers and has been confirmed as the major cause of this cancer.

How HPV Is Transmitted. HPV is spread primarily by having sex with an infected partner. It should be noted, however, that most sexually active young women become infected with this virus, but only 10% remain infected for more than five years. Only those infected for longer than five years have a higher risk (about 50% above normal). Other factors are then needed to trigger the disease.

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 growth. Once they are blocked, cell growth 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. Other low-risk HPV genetic types are 40, 42, 43, 44, 54, 61, 70, 72, 81. These viral types 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.)

Of the high-risk types, HPV type 18 and HPV 16 have long been known to be particularly dangerous. These two genetic types and six others (31, 33, 35, 45, 52, and 58) account for 95% of HPV-related cervical cancers. Other high-risk types are 39, 51, 56, 59, 68, 73, and 82. All are associated with moderate dysplasia (CIN II) and carcinoma in situ (CIN III). Types 26, 53, and 66 are considered high-risk.

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 Chlamydiatrachomatis, a sexually transmitted infection, and HPV. (Chlamydia trachomatis should not be confused with Chlamydia pneumoniae, 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.

Risk Factors

According to the American Cancer Society, more than 10,000 new cases of invasive cervical cancer will be diagnosed in the US in 2005. However, the number of new cervical cancer cases has been declining steadily over the past decades. Fifty percent of cervical cancer diagnoses occur in women between 35 and 55 years of age, and slightly more than 20 percent occur in women over 65 years of age.

Some women (15%) develop cervical cancer before the age of 30. Although cervical cancer is rare in women under 20, there has been an increase in cancer rates in younger women. Many young women are infected with multiple types of HPV, which can increase their risk of getting cervical cancer. If young women with early abnormal changes do not have regular examinations, they are at high risk for localized cancer by the time they are age 40 and for invasive cancer by age 50.

Although it is the most preventable type of cancer, cervical cancer is ranked as the second most common cause of female death. Each year it kills an estimated 3,700 women in the US and nearly 300,000 women worldwide.

In the United States, cervical cancer mortality rates plunged by 74 percent between 1955 and 1992 thanks to increased screening and early detection with the Pap test.

Socioeconomic and Ethnic Factors

Although the rate of cervical cancer has declined in both Caucasian and African American women over the past decades, it remains much more prevalent in African Americans, and their death 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 invasive cervical cancer as Caucasian women due to a lower rate of screening. This lower rate, particularly in immigrants from Mexico, may be due to cultural beliefs that Pap smears might be an "admission of immorality." Fortunately, evidence in 2002 suggests that screening is increasing in young Hispanic women.

Specific Risk Factors for Human Papillomavirus

The human papillomavirus (HPV) is the primary cause of cervical cancer. Between 12% and 46% of American women carry the virus. The risk for cervical cancer in infected women appears to be highest in those infected with HPV for more than six months. In most people, the virus goes away within a year. However, it persists in about 10% of infected women.

High Sexual Activity. In adults, the most important risk factor for HPV is sexual activity with an infected person. Women most at risk for cervical cancer are those with a history of multiple sexual partners, sexual intercourse at 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 many infections in addition to human papillomavirus.

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, making women more susceptible to HPV.

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.

Risk Factors for HPV in Children and Infants. HPV also can occur in children and even newborns. The virus may also be transmitted by an infected mother. In children, HPV is usually the harmless form that cause skin warts.

Genetics

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.

Use of Oral Contraceptives

A number of studies, including a major analysis, have reported a strong association between cervical cancer and long-term use of oral contraception (OC). Women who have taken OCs for more than ten years have a much higher risk of HPV infection (up to four times higher) than those who do not use OCs. (Women taking OCs for less than five years have no significantly higher risk.) The reasons for this risk from OC use are not entirely clear. Women who use OCs are less likely to use a diaphragm, condoms, or other methods that offer some protection against sexual transmitted diseases, including HPV. Some experts also suggested that the hormones in OCs might facilitate entry of the HPV virus in the genetic material of cervical cells.

Having Many Children

Studies indicate that having many children increases the risk for developing cervical cancer, particularly in women with HPV.

Smoking

Several studies have associated smoking with a higher risk for precancerous changes (dysplasia) in the cervix and for progression to invasive cervical cancer. Secondhand smoke is also linked to increased risk for cervical cancer tumors. It is not clear if this association is due to cigarette smoke’s direct cancer-causing effects or general damage to the immune system. Cigarette smokers are also deficient in folate, a B vitamin. Folate deficiency may play a role in the development of dysplasia.

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.

Prognosis

The following are some examples of the time it takes for early stages of cervical dysplasia 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), 16% will progress to the next stage in two years; 25% will progress 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. In general, 71% of women with invasive cervical cancer survive for five years or more. African American women tend to have poorer 5-year survival rates than Caucasian women, although survival rates have significantly increased in African American women in recent 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%. Experts say universal screening could 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 5-year survival rates may drop to 50% and below, depending on how much it has spread and the type of cancer cell.

Identifying what type of HPV a woman has may help determine outlook and the severity of cervical cancer. For example, 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.

Other biochemical markers in the body may also help predict outcome and treatment. For example, women with cervical cancer who have high levels of an enzyme called cyclooxygenase (COX-2) may require more aggressive treatments than those with low levels.

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.

Symptoms

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.

Prevention

The best way to prevent cervical cancer is to avoid getting infected with human papilloma virus (HPV). Because HPV is sexually transmitted, practicing safe sex and limiting the number of sexual partners can help reduce risk. Vaccines are being developed that may protect against some cancer-causing HPV strains. Regular Pap tests remain the most effective way of preventing the development of invasive cervical cancer.

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.

Male Circumcision

A 2002 study reported that men who are circumcised have a lower risk for carrying HPV and therefore reduce the risk for cervical cancer in their female partners.

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.

Although vitamin E is a fat-soluble vitamin, there are no known toxic effects of megadoses.

Click the icon to see sources of food which contain vitamin E.

Click the icon to see the benefits of vitamin C.

Click the icon to see sources of food which contain vitamin C.

• 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.

Vaccines against HPV

Several cervical vaccines are now in development. These vaccines target HPV 16 and HPV 18, the most dangerous strains of human papilloma virus. HPV 16 and 18 cause 70% of cervical cancers. A vaccine called Gardasil has been tested in over 12,000 uninfected women in 13 countries and provided complete protection against HPV 16 and 18. Gardasil also protects against HPV 6 and HPV 11, which cause genital warts. However, even if this vaccine is approved, patients will need to receive regular screening tests because the vaccine does not protect against all HPV strains that can cause cervical cancer.

Patients in the Gardasil study received three vaccine shots over a six month period. Researchers think that the best time to vaccinate girls is before they become sexually active and risk being exposed to sexually transmitted viruses. Another type of cervical cancer vaccine (Cervarix) is also being investigated. It protects against HPV 16 and 18, as well as the cancer-causing strains HPV 31, 45, 52. It does not protect against genital warts.

Diagnosis

The changes that lead to cervical cancer develop slowly. Screening tests performed during regular gynecologic examinations can detect early changes.

Pap Smear

Every year in the US about 50 million women have a Papanicolaou test (the Pap smear). Use of the Pap smear has reduced the annual death rate from cervical cancer from 26,000 in 1941 to 3,700 in 2005. Forty percent of the fail to follow-up for retesting and treatment.

Most cases of cervical cancer occur in women who have not had regular Pap tests.

The Procedure. The most accurate results seem to be obtained 12 to 14 days after menstruation begins. Women should not douche or have intercourse within 48 hours of the test. Douches and spermicidal creams may clean out abnormal cells and interfere with the results of a Pap smear. (In general, douching is not recommended at all.) A Pap smear is usually painless, although some women may have some discomfort.

• The test is done in a doctor's office. The woman removes her clothes from the waist down and puts on a medical gown. She lies on her back on the examination table, bends her knees, and puts her feet in supports (called stirrups) at the end of the table.
• A doctor inserts a metal device into her vagina to widen it.
• Using a spatula, brush, or both, the doctor gently scrapes the surface of the cervix, and sometimes the upper vagina, to gather living cells. The doctor will also 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). Using both a brush and spatula helps gather better samples to detect the presence of cancer.
• The cells are preserved, stained for microscopic viewing, and then analyzed under a microscope by a specialist known as a cytopathologist.

A Pap test is a simple, relatively inexpensive procedure that can easily detect cancerous or precancerous conditions.

Reliability and Accuracy. Over the course of a lifetime of regular screening, a woman faces a 40% chance of being told her Pap smear is abnormal. The Pap smear is not, however, a perfectly reliable measure of a woman's risk for cervical cancer.

In general, about 10% of Pap smears have abnormal results, but only about 0.1% of the women who have these results actually have cancer. In most cases, abnormal cells are low grade and not likely to progress to cancer or are due to benign conditions, including natural cell changes after menopause.

No test is 100% accurate, and it is possible for the Pap smear to miss the presence of cancer. However, it should be noted that if abnormal cells are missed on one test they are likely to be spotted during the next one without a significant danger.

Liquid-Based Pap Test

Newer, thin-layer liquid based tests (ThinPrep, SurePath) use the original cervical sample, which is rinsed in a special solution to thin the mucus (rather then dried). The result is a clear, clean sample that may be able to accurately reveal abnormal cell. The fluid can also be examined for evidence of HPV and other early abnormalities. Some--but not all--studies have found this test to be more accurate than the standard Pap smear.

Computerized Pap Test Systems

New tests and methods have been developed to improve the accuracy of the Pap smear in detecting cancer cells. For example, there are several computerized Pap test systems (FocalPoint, PAPNET) that are used to rescreen the original smear. These systems are either used to detect abnormal samples that may have been missed by manual review methods or are used in place of a human cytotechnologist. According to the US Preventive Services Task Force (USPSTF), there is not yet enough evidence to know whether or not computerized methods are superior to conventional Pap testing.

Tests for Human Papilloma Virus (HPV)

The high-risk types of human papilloma virus (HPV) are now a known cause of cervical cancer. Tests are now available for identifying these types. Their presence is a strong predictor of high-grade aggressive abnormalities or cancer itself. Testing for HPV does not replace the Pap smear, but when used adjunctively with the Pap test this screening combination may help to more accurately detect cervical cell abnormalities than either test alone.

In 2003, the FDA approved the Hybrid Capture 2 (HC2) HPV DNA test for use with the Pap test for cervical cancer screening in women over 30 years of age. The HPV DNA test can identify 13 types of the high-risk HPV that are most frequently implicated in the development of cervical cancer. At this time, the test is recommended as an adjunct to the Pap test but not as the sole method for primary screening.

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 younger 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 doctors may also be able to spot abnormal blood vessel patterns indicative of cancer areas on the cervix. This is an inexpensive and simple test and in one 2002 study identified 70% of aggressive cancers.

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.

Other Investigative 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. In addition, they are looking for biologic markers to improve diagnosis, such as specific proteins that indicate the presence of cancer cells.

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.

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 doctor aims a light at the cervix.
• The doctor 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 suspicious areas, of the endocervical canal (the inner part of the cervix and uterus), and any abnormal-looking areas. This may cause cramping or pinching.

Click the icon to see an image of a colposcopy-directed biopsy.

After the colposcopy, the woman may have a brownish discharge from an iron solution called Monsel's solution, which the doctor applies to prevent bleeding. The doctor 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.

Treatment for CIN and Carcinoma in Situ

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

• CIN I often goes away on its own. Careful follow up is required to make certain that the Pap smear and colposcopic exam return to normal.
• CIN II or CIN III may turn into invasive cancer if the suspicious area is not removed. This is often done using an outpatient technique called loop electrosurgical excision procedure (LEEP). [See next section.]
• If extensive areas of CIN II or III cannot be entirely seen with colposcopy or if they spread into the mucous membrane in the cervical canal, a more aggressive procedure called conization (cone biopsy) may be required.

The cold cone biopsy is a surgical procedure that requires general anesthesia. It is performed when there are severe precancerous changes in the cervix.

Treatment for Adenocarcinoma in Situ. An adenocarcinoma is cancer inside tissue that looks like or functions as a gland. (A gland is a group of cells that secretes a substance to be used by or removed from the body.) Adenocarcinomas tend to be more aggressive than the more common squamous carcinoma in situ, which grow in the lining of tissue (mucous membrane). Some evidence suggests that adenocarcinomas develop 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 to cut 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.

Some experts feel that the only downside of LEEP is its simplicity. That is, doctors 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 suggest that the cells may become invasive.

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. As in LEEP, patients should be monitored closely if patients are infected with HPV virus or the biopsies on the cervical tissue removed show aggressive-grade cells.

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.

A technique called frozen section examination (FSE) freezes the margins of the area being removed. Studies suggest that FSE allows immediate and precise evaluation of areas that may harbor invasive cancer cells, and may be important addition to this procedure in women with high-grade CIN.

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 doctor'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.

Click the icon to see an image of cervical cryosurgery.

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.

Treatment 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.

Imaging Tests to Determine Extent of Tumor Spread. 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.

CT stands for computerized tomography. In this procedure, a thin x-ray beam is rotated around the area of the body to be visualized. Using very complicated mathematical processes called algorithms, the computer is able to generate a 3-D image of a section through the body. CT scans are very detailed and provide excellent information for the doctor.

• 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).

Click the icon to see an image of intravenous pyelography.

Click the icon to see an image of 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.

Click the icon to see an image of cystoscopy.

• Sigmoidoscopy is used to evaluate the rectum. (Both this procedure and a cystoscopy involve the insertion of a tube with a lighting device for viewing and manipulating the internal areas.)

Click the icon to see an image of sigmoidoscopy.

• 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.

Click the icon to see an image of a MRI.

Sentinel Node Biopsy. 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.

A 2002 study reported that this technique was able to detect cancer that had spread in 87.5% of cases. More investigation is required before it can be widely used.

General Treatment Guidelines

Once diagnosed, cervical cancer (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.

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.

Stage 0 and Treatments

Stage 0 is 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 (Including Locally Advanced Cancer) and Treatments

Stage I is invasive cancer, but the tumor confined is confined to the cervix. This stage is further categorized as IA and IB.

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

• In stage IA1 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. Trachelectomy has been investigated for women who want to preserve fertility.
• 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.

Note on Stage IA2 through IIA: 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 IB and Locally Advanced Cancer. 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.

• In stage IB1 the tumor is typically visible (not usually 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 radiation therapy with concurrent platinum-based chemotherapy is reasonable. Some women in stage IB may be given combinations of radiation and surgery, although the benefits of such combinations are unclear for most women, particularly given a higher risk for severe side effects.

Note on Locally Advanced Cervical Cancer: Stages IB2 through IVA are often referred to collectively as locally advanced cancer and are frequently treated similarly. In addition to standard treatments, notably radiotherapy with concurrent platinum-based chemotherapy, experimental approaches for some women with locally advanced cervical cancer employ radiation therapy with hyperthermia (high heat often provided by ultrasound) and neoadjuvant (preoperative) chemotherapy and radical surgery.

Stage II and Treatments

Stage II invasive cancer extends beyond the cervix, but not does not involve the pelvic side wall. This stage is further categorized as IIA and IIB.

Stage IIA. 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 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.

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

Stage III and Treatments

In 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 and Treatments

In 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%.

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

Stage IVB. 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 and Treatments

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 only local areas. (This involves 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 option if it is technically possible, generally if patients did not have it previously. If cancer has metastasized, platinum-based chemotherapy is reasonable. Other agents may be useful under certain circumstances.

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

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.

Surgery

In the early stages of cervical cancer, surgery is often the preferred primary treatment approach since it preserves normal sexual function. Some patients desiring fertility who have early stage I cancer may be candidates for cervical cone biopsy.

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.

Click the icon to see an illustrated series detailing a hysterectomy.

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 dysfunction, 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.

Trachelectomy.An experimental procedure called trachelectomy is being investigated for preserving fertility in certain women in 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 a few hundred of these procedures have been performed to date. Women should also realize that conception rates are still lower than normal. And even if they can get pregnant, there is a very high risk for miscarriage because the cervix is weakened. Larger and longer-term studies are needed to confirm its long-term safety.

Radiation

Radiation therapy is an alternative approach for early stage cervical cancer. Radiation with concurrent with cisplatin-based chemotherapy is now the standard treatment for locally advanced cervical cancer. Radiation therapy 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.

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.

Advanced methods for targeting radiation more precisely are now available that limit the damage to healthy tissue. They include 3-D conformal radiation and intensity-modulated radiation therapy (IMRT):

• 3-D conformal techniques use computers and a three-dimensional image of the cervix to provide precise targeting of the tumor using multiple high-dose radiation beams.
• IMRT also uses 3-D techniques and employs very thin and precise beam at various intensities.

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). Bowel obstruction is an uncommon complication. 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.

Click the icon to see an image of the female anatomy.

Investigative temporary silicone implants or a noninvasive device called the belly board may protect the small intestine during radiation therapy and help reduce complications.

Radiation itself may increase the risk for later development of cancer in the area surrounding the treated tissue. Although newer more precise radiotherapy approaches should reduce this risk, there is some concern that IMRT may double the incidence of secondary cancers over time compared to 3-D conformal techniques. This is of particular concern in younger patients.

Radiation and Hyperthermia. Investigators are studying hyperthermia (use of high heat often provided by ultrasound) in combinations with radiation therapy. This approach has shown some promise in achieving significant response rates in small studies. Comparison studies are important to determine if this approach would be as beneficial with radiation therapy as concurrent chemotherapy.

Chemotherapy

Chemotherapy uses cell-killing drugs called cytotoxic agents to destroy widespread cancer cells that have spread from the primary tumor and can no longer be treated with surgery or radiation.

For many years, chemotherapy was only used to reduce symptoms in women with very advanced disease. Today, platinum-based chemotherapy agents (see below) are being used in many situations for cervical cancer such as:

• In combination with radiation therapy to improve survival rates in certain women, including some with locally advanced cancer.
• In some women with locally advanced cancer to reduce tumors to the point where the cancer may be operable.
• When cancer has spread (metastasized), mostly to reduce symptoms such as pain.

Platinum-BasedAgents. One of the most effective types of chemotherapy drugs for cervical cancer is cisplatin. Cisplatin is a platinum-based drug, and is one of the standard drugs used for cervical cancer. (Carboplatin is another.) Other platinum agents, such as nedaplatin, are under investigation.

Cisplatin enhances the effectiveness of radiation in patients with more advanced disease stages. (This is called a radiation enhancer or sensitizer.) Combining certain chemotherapy drugs with radiation therapy may destroy more cancer cells. Combination therapy is an important treatment strategy for many patients with late-stage cervical cancer. There is some evidence that a combination of platinum agents plus paclitaxel and other single agents may work better than platinum agents alone in the treatment of metastatic disease.

Topotecan, a chemotherapy drug that interferes with the growth of cancer cells, is now showing promise in early studies as an effective radiation enhancer.

Other Agents. Other drugs, mostly used in combinations, have also been investigated with some promise. They include with epirubicin, irinotecan, paclitaxel, bleomycin, mitomycin, vinorelbine, gemcitabine, and doxifluridine.

Administration. Chemotherapy may be given by mouth or as an injection. This may be done at a medical center, doctor'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 given 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, side effects are inevitable. Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include the following:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and in most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy results in a major or complete reduction in nausea and vomiting.
• Diarrhea.
• Temporary hair loss.
• Weight loss.
• Fatigue.
• Anemia.
• Depression.

Complications. Serious short- and long-term complications can also occur and may vary depending on the specific agents used. They include:

• Increased chance for infection. Chemotherapy suppresses the immune system.
• Severe drop in white blood cell count (neutropenia). Certain agents, such as taxanes, pose a higher risk for this than other chemotherapeutic drugs. White blood cell count may be improved with the addition of a type of drug called granulocyte colony-stimulating factor (either filgrastim and lenograstim).
• Liver and kidney damage.
• Abnormal blood clotting (thrombocytopenia).
• Allergic reaction, particularly to platinum-based agents. (A simple skin test in under investigation that may identify people with a potential allergic response.)
• Menstrual abnormalities. These are common. Premature menopause occurs in about 30% of women, particularly in those over 40.
• Secondary cancers such as leukemia (rare).
• Problems in concentration, motor function, and memory, which may be long-term. Between a quarter and a third of women report such problems. This may be due to a drop in estrogen levels after treatments.

Resources

• www.cancer.gov -- National Cancer Institute
• www.cancer.org -- American Cancer Society
• www.acog.org -- American College of Obstetricians and Gynecologists
• www.ashastd.org -- The American Social Health Association
• www.arhp.org -- Association of Reproductive Health Professionals
• www.nccc-online.org -- National Cervical Cancer Coalition
• www.cervicalcancercampaign.org -- Cervical Cancer Public Education Campaign
• www.thegcf.org -- Gynecologic Cancer Foundation
• www.gothpv.net -- Information on HPV

References

Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis. 2005;191(2):182-192.

Leyden WA, Manos MM, Geiger AM, Weinmann S, Mouchawar J, Bischoff K. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9):675-683.

Trimble CL, Genkinger JM, Burke AE, Hoffman SC, Helzlsouer KJ, Diener-West M, et al. Active and passive cigarette smoking and the risk of cervical neoplasia. Obstet Gynecol. 2005;105(1):174-181.

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