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• Highlights
• Introduction
• Causes
• Risk Factors
• Prognosis
• Symptoms
• Prevention
• Diagnosis
• Treatment for CIN and Carcinoma in Situ
• Treatment for Cervical Cancer
• Treatment for Invasive Cervical Cancer
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Cervical cancer

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of cervical cancer.

Alternative Names

Dysplasia; Human papillomas virus; Pap smear

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 U.S. 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 women who have a Pap smear 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 test results are obtained 12 - 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.

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, 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 cells. 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. A rigorous 2006 review of 56 studies found that liquid-based tests were no more accurate than conventional Pap smears.

Current Pap Smear Screening Recommendations The US Preventive Service Task Force (USPST), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) have all released guidelines for cervical cancer screening. ACOG and ACS have established separate screening criteria for women below and above 30 years of age. Although there are some small differences between these three sets of guidelines, they generally make similar recommendations as summarized below: Recommendations for Initial Screening. Women should begin to undergo Pap tests within 3 years of onset of sexual activity or at age 21 (whichever comes first). Women with no 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. Women Up to Age 30 . Women under age 30 should receive annual screening with the conventional Pap smear. The American Cancer Society (ACS) offers the alternative of screening every 2 years using the newer liquid-based testing. HPV testing is not recommended for this age group because HPV infections in women under age 30 tend to resolve on their own. Women Age 30 and Over . Women in this age group who have received three consecutive negative (normal) annual Pap tests have two screening options: Screening with standard or liquid-based Pap tests every 2 - 3 years. Women in high-risk groups (DES exposure, HIV infection, weakened immune system, or previous diagnosis of cervical cancer) should continue to receive annual tests. Screening with Pap test plus HPV DNA test. If a woman tests negative on both of these tests, then she can be rescreened no more frequently than once every 3 years. If one of the tests if positive, she will need to be screened more frequently. Elderly Women. In its 2003 guidelines, the U.S. Preventive Service Task Force recommended against routine screening in women over age 65 with low or no risk factors. (The ACS recommends stopping at age 70, while ACOG declines to set an upper age limit.) Such women have had at least three previous normal screenings and have had no abnormal results for at least 10 years. According to the guidelines, older women should be screened if they have not been screened before or if there is a possibility that they have not been screened (for example, if the woman is from a country that does not do routine screening). However, a 2006 study of more than 15,000 postmenopausal women recommended continued screening for elderly women who are sexually active but not monogamous. (Women in the study had a uterus.) The researchers note that about 25% of new cervical cancer cases, and 41% of cervical cancer deaths, occur among women 65 years and older. After a Hysterectomy. The 2003 guidelines recommend against routine screening for women who have undergone a total hysterectomy for benign causes. Women who have had a hysterectomy that preserves the cervix (called a supracervical hysterectomy) should continue with Pap screening. Follow-up After Normal Results If Pap smear results are normal for 3 consecutive years, most expert groups recommend a Pap test every 2 - 3 years thereafter in most women over 30 years of age. (The ACS suggests that such women wait until they are 30 before extending the interval to 3 years.) Both the ACS and the American College of Obstetricians and Gynecologists (ACOG) recommend that annual screening should continue in women in high-risk categories. High risk categories may include the following, depending on the medical group: 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. Follow-up After Abnormal Results Any abnormal result, even a mild abnormality, requires follow-up visits and additional tests. The extent of these tests depends on the degree of abnormalities.

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 a 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.

Classifying Cervical Cells and Determining Further Testing The cells viewed in a cervical smear sample are classified on a scale representing the spectrum of cell changes from normal to cancerous. The smear is first characterized as either "normal" or "abnormal." Once abnormal cells are identified, the doctor must decide whether the patient needs only repeat Pap smears, a test for the HPV virus, or colposcopy (a procedure used to magnify the cervix and permit detection of lesions for biopsy). To help the doctor make the decision, the abnormal cells are divided into categories, depending on the degree of abnormality. These classifications are based on the 2001 Bethesda System (TBS) which is formulated to standardize the reporting of Pap test results. Atypical Squamous Cells (ASC). Atypical squamous cells (ASC) are mildly abnormal cells on the surface of the cervix. They may simply represent inflammation. Over 80% of these cells normalize, but unfortunately, between 5 - 17% of these women have a chance for having CIN II and III dysplasia (potentially invasive cells). Experts have now further categorized ASC as the following: ASCUS. This category identifies atypical squamous cells of undetermined significance. They are the lowest risk abnormal cells. Women with ASCUS should be tested for human papillomavirus infection (HPV). If results indicate they are infected with HPV, they should be given colposcopy, a more invasive diagnostic procedure to determine if the condition is actually at a more aggressive stage. If they do not have HPV they are simply monitored with repeat Pap smears. ASC-H. This category refers to the presence of atypical squamous cells, but a doctor cannot exclude possible high-grade squamous intraepithelial lesions. Such women have a 24 - 94% chance of having CIN II and III. All are referred for colposcopy. Among those with ASC, immunosuppressed women and those with high-risk human papillomavirus infections are at higher risk for CIN II and III and should always be given colposcopy. Postmenopausal women with normal immune systems have a lower risk than younger women. It should be strongly noted, however, that actual risk for cervical cancer in general in women with ASC is only 0.1 - 0.2%. Low Grade Squamous Intraepithelial Lesions (LSIL). Low-grade squamous intraepithelial lesions (LSIL) are typically associated with human papillomavirus changes, with or without early dysplasia (CIN I). Between 15 - 30% of women with LGIL, however, may have CIN II or III on biopsy. Women with LSIL are either monitored with repeat Pap smears or given colposcopy. Experts recommending colposcopy argue that these are high-risk women and there is a risk for delaying a diagnosis of cancer using only repeat Pap smears. High-Grade Squamous Intraepithelial Lesions (HSIL). High-grade squamous intraepithelial lesions (HSIL) are associated with moderate dysplasia and other CIN II or III. Such women are always referred to colposcopy for biopsy. Even if colposcopy results report only CIN I, over a third of these women are likely to have CIN II or III. Experts, therefore, recommend a careful review of the tests in such cases. Pregnancy poses a problem since it increases the chance in HSIL for both normal and abnormal results. In nonpregnant women, particularly when fertility is not an issue, immediate treatment with loop electrosurgical excision procedure (LEEP) may be appropriate. Atypical Glandular Cells (AGS). Atypical glandular cells are uncommon, but pose a higher risk for cancerous changes than ASC or LSIL. Between 9 - 54% have some CIN, between 0 - 8% have carcinoma in situ, and between 1 - 9% have invasive cancer. 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.

The Procedure. Colposcopy can be performed in a doctor's office without anesthesia in 10 - 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.

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 1 - 2 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.

• Review Date: 9/1/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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