Screening for cervical cancer

INTRODUCTION — The Pap smear is a common test used to screen women for cervical precancer or cancer. However, most abnormal Pap smears are not due to cancer, but rather caused by infection or low estrogen levels.

This topic reviews the anatomy of the cervix, factors that increase a woman's risk of having cervical precancer or cancer, tests to detect cervical abnormalities, and a description of both normal and abnormal Pap smear results. A separate topic is available that discusses treatment of abnormal Pap smears. (See "Patient information: Treatment of abnormal Pap smears").

ANATOMY OF THE CERVIX — The cervix is located at the lower end of the uterus (show figure 1). The surface of the cervix includes several layers of cells. Squamous cells make up the outer layer of the cervix and vagina.

The cervix also includes glandular (also called columnar) cells, which line the opening in the cervix. The region where the two cell types meet is called the "transformation" zone (show picture 1). The transformation zone is the region most likely to contain abnormal cells.

If more than one third of the layers contain abnormal cells, this is called high grade squamous intraepithelial lesion (HSIL or HGSIL) (show figure 2).

What is a Pap smear? — A Pap smear is a method of examining cells from the cervix. The traditional Pap smear (named after Dr. Papanicolaou) involved smearing the cervical cells onto a glass slide. More recently, liquid-based tests (eg, ThinPrep, SurePath) have become available; these tests place the sample of cervical cells into a vial containing a liquid preservative. In both types of test, the cells are viewed with a microscope to detect abnormalities.

Cervical cells may appear abnormal for a variety of reasons. For example, a woman may have low estrogen levels or a cervical infection, or she may have a precancerous area or even cervical cancer. If the Pap smear is abnormal, further testing is needed to determine what the abnormality is and if treatment is needed.

Who should have a Pap smear? — The first Pap smear should be done by age 21 years. For most women, a Pap smear is recommended every one to three years. For women who have a past history of abnormal Pap smears or who have risk factors for cervical cancer, testing is recommended once per year (see "Risk factors for cervical cancer" below).

Women who are older than 30 years who have no risk factors, a negative Pap smear three years in a row, and a negative HPV test may choose to have a Pap smear and HPV testing every three years rather than every year (see "HPV testing" below). Most experts feel that women who are at low risk for cervical cancer (eg, no past history of an abnormal Pap) can discontinue Pap smears by age 65 to 70 years.

How are Pap smears obtained? — Pap smears are performed during a pelvic examination. To perform the test, a healthcare provider uses an instrument (speculum) to view the cervix, which is located at the lower end of the uterus (show figure 1). The provider sweeps the surface of the cervix and inner cervix (called the endocervical canal) with a soft brush or small spatula to collect cervical cells. This is not painful.

Pap smear accuracy — Most Pap smears can accurately identify women with abnormal cervical cells. However, the test is not perfect, and it misses between 5 and 25 percent of women with abnormalities. These women are said to have a false negative result. There are several important points to consider when discussing false negative results: Many false negative results are due to difficulty in collecting a sufficient number of cervical cells, not errors in reading the smear. It may be difficult to collect cervical cells if the cervix is hard to find during a pelvic examination, if the abnormal area is very small or high up inside the cervix, if only a few cervical cells are obtained, if the specimen dries too quickly, if the patient douches or has sexual intercourse before the examination, or if the woman is bleeding or has an infection at the time of the Pap smear. If a woman has a normal result three years in a row, then it is unlikely that an abnormality has been missed. The frequency of screening for cervical cancer can then be spread out (see "Who should have a Pap smear?" above). If a new lesion develops in a woman who is only tested every three years, it will be found before it becomes serious because it takes years for a new abnormality to develop into a high-grade precancer or cervical cancer. It usually takes many years for precancerous cervical cells to progress to cancer, and progression to cancer does not always occur.

RISK FACTORS FOR CERVICAL CANCER — The most important risk factor for cervical cancer is infection with the human papillomavirus (HPV). Other factors that increase the risk of cervical cancer include sexual intercourse, use of tobacco (eg, cigarettes), use of birth control pills, and a weakened immune system (eg, due to HIV infection or certain medications) (show table 1).

Human papillomavirus — Infection of the cervix with certain types of human papillomavirus (HPV) is the most significant risk factor for cervical abnormalities and cancer. Over 100 different types of HPV have been identified, however not all types infect the cervix or cause cancer. Researchers have labeled the HPV types as being high or low risk for causing cervical cancer. HPV types 6 and 11 can cause warts and are low-risk types because they rarely cause cervical cancer; types 16 and 18 are considered high-risk types because they may cause cervical cancer in some women. (See "Patient information: Condyloma (genital warts) in women").

HPV is spread by direct skin-to-skin contact, including sexual intercourse, oral sex, anal sex, or any other contact involving the genital area (eg, hand to genital contact). It is not possible to become infected with HPV by touching an object, such as a toilet seat.

Most persons who are infected with HPV have no signs or symptoms. Most HPV infections are temporary and resolve within two years. When the virus persists (in 10 to 20 percent of cases), there is a higher likelihood of developing cervical cell abnormalities and cancer. However, it usually takes several years for HPV infection to cause cervical cancer (see "HPV testing" below).

Sexual history — Cervical cancer is rare in women who have never had sexual intercourse. Cervical cancer is more common in women who have had more than one sexual partner or whose partners have more than one sexual partner. Other risk factors include: HIV infection, sexual intercourse before age 17, or a history of sexually transmitted diseases (eg, genital herpes or Chlamydia).

Tobacco use — Smoking cigarettes increases the risk of cervical cancer and precancer by up to seven times that of women who do not smoke. This is believed to occur because cancer-causing products from tobacco are secreted into the cervical mucous. Stopping smoking can decrease this risk. (See "Patient information: Smoking cessation").

Birth control with estrogen — Woman who use a birth control method that contain estrogen (eg, pills, patch) have a slightly higher risk of cervical precancers and cancers compared to women who do not take them (show table 1). The risk of cervical cancer related to birth control is small, and is related to infection with HPV. Thus, women who take a birth control with estrogen but are not infected with HPV have no increased risk of cervical cancer or precancer.

The reason that oral contraceptives increase the risk of cervical cancer is not clear. Higher levels of estrogen may causes changes in the cervix that increase the growth of cells that develop as a result of the HPV infection.

However, birth control with estrogen has a number of benefits, including a reduced risk of ovarian and uterine cancer and decreased pain and bleeding with menstrual periods. Women should discuss all the risks and benefits of this type of birth control with a healthcare provider. (See "Patient information: Hormonal methods of birth control").

Weakened immune system — Normally, the immune system works to protect the body from illness and infection, including the infection caused by human papillomavirus. Women with a weakened immune system have a significantly increased risk of cancers and precancers of the cervix.

A number of factors can weaken the immune system, including HIV infection, prolonged use of glucocorticoids (eg, prednisone), and use of medications to prevent rejection after organ transplantation.

PAP SMEAR RESULTS — The information reported in a Pap smear is described in table 2 (show table 2A-B). Pap smear results may be reported as:

Negative — Pap smears that have no abnormal, precancerous, or cancerous cells are labeled as "Negative for intraepithelial lesion or malignancy".

Smears that are negative can show other conditions, such as a vaginal infection (Trichomoniasis, yeast, herpes, or bacterial vaginosis) or cellular changes related to vaginal dryness, radiation therapy, or an intrauterine device (IUD) string. In some situations, further testing and/or treatment are needed.

Abnormal results — A number of medical terms are used to describe abnormalities of the cervix, including dysplasia, squamous intraepithelial lesion, and intraepithelial neoplasia. These terms all mean that the abnormality is confined to the surface or glandular lining of the cervix.

Follow up testing — Further testing is often needed after an abnormal Pap smear. The most common tests include HPV testing and colposcopy.

HPV testing — HPV testing is recommended only in particular circumstances: If the Pap smear shows a specific abnormality (for example, atypical squamous cells of uncertain significance, or ASC-US), HPV testing is then performed. This is called reflex testing.

Testing every woman for HPV is not recommended because of the risk of false positive results (when the HPV test was falsely positive and the Pap smear was negative). It is likely that many women develop HPV infections that resolve spontaneously. Having a false positive result would lead to unnecessary follow-up testing and anxiety for many women.

Colposcopy — Colposcopy is an office procedure that allows a clinician to closely examine the cervix. It is commonly performed after an abnormal Pap smear. Colposcopy is performed similar to a pelvic examination, while the woman lies on an exam table. A speculum is used to view the cervix, and the viewing device (called a colposcope) remains outside the woman's body (show picture 2).

The colposcope magnifies the appearance of the cervix 10 times. This allows the clinician to better see the location and size of any abnormalities, and also to see any changes in the capillaries (small blood vessels) on the surface of the cervix. Capillary changes are not detected by cervical cytology or HPV tests, but are important signs of the severity of cervical abnormalities.

Using the colposcope, a small piece of the abnormal area can be removed (biopsied). Anesthesia (numbing medicine) is not needed because the biopsy causes only mild discomfort or cramping. The biopsy is then examined with a microscope by a physician (called a pathologist). The results of the biopsy are usually available within one to two weeks.

Some women also need to have a biopsy of the inner cervix during colposcopy; this is called endocervical curettage. Endocervix refers to the inner cervix and curettage means scraping.

ATYPICAL SQUAMOUS CELLS (ASC) — A Pap smear may be read as atypical when cervical cells are not completely normal but are not thought to be precancerous. Further testing of ASC is suggested because some women (5 to 17 percent) have a precancerous lesion that is seen when colposcopy is performed. ASC is subdivided into ASC-US and ASC-H; ASC-H is more likely than ASC-US to be caused by a precancerous change.

ASC-US — There are three options for follow up of a single ASC-US result: Perform HPV testing. This is the preferred follow up for ASC-US. HPV testing can often be done at the same time as the Pap smear. This is convenient because a woman does not have to return for a second visit (see "HPV testing" above).

Women who test positive for high-risk HPV types are referred for colposcopy because they are at greater risk of having a precancerous lesion.

Women who test negative for HPV are not likely to have cervical precancer. These women should have a repeat Pap smear in one year. In most cases, the ASC-US resolves on its own. Repeat the Pap smear in four to six months. If this Pap is normal, it is repeated every four to six months until there have been two normal tests in a row. If the woman has two ASC-US results, she should have colposcopy.

For postmenopausal women, use of an estrogen treatment in the vagina for one month may be recommended after one ASC-US result; low estrogen levels in the vaginal and cervical tissues can cause mild cellular abnormalities that often revert to normal after estrogen treatment. Colposcopy should be performed if the woman has a second ASC-US result after use of estrogen therapy. Have colposcopy. This approach is preferred for women who are HIV positive or who have a weakened immune system because of the higher risk of a precancerous lesion (see "Colposcopy" above).

ASC-H — This finding requires further testing with colposcopy (see "Colposcopy" above).

LOW-GRADE SQUAMOUS LESION (LSIL) — These are mild cellular changes. Further testing is almost always recommended for women with LSIL because 15 percent of women with LSIL have a precancerous lesion that was not detected by the Pap smear.

A small number of women with low-grade changes will develop cancer over a period of several years if no treatment is performed. A large percentage (50 to 90 percent) of women with low-grade changes do not require treatment because the abnormality resolves on its own.

Low-grade abnormalities may be described with other names, including low-grade squamous intraepithelial lesions (LSIL), cervical intraepithelial neoplasia, grade 1 (CIN 1), and mild dysplasia.

Follow up of LSIL — Colposcopy is recommended for women with low-grade lesions (LSIL) (see "Colposcopy" above). Determining the size and location of the lesion with colposcopy can help to decide whether to treat the lesion or follow it over time. Large lesions are less likely to heal without treatment. Observing the extent and severity of the lesion with colposcopy is useful for establishing a baseline in women who are not treated.

However, LSIL in postmenopausal or adolescent women may be approached differently. A repeat Pap smear or HPV test may be recommended for adolescents; if the HPV is positive or the Pap smear continues to be abnormal, the adolescent is usually referred for colposcopy. Postmenopausal women may be treated with a course of estrogen cream, as described above (see "Atypical squamous cells (ASC)" above).

Treatment of LSIL — There are three options for management of LSIL: Close follow-up with HPV testing after 12 months or repeat Pap smear at six and 12 months. Colposcopy is performed if abnormalities persist or worsen (see "Follow up testing" abovesee "Follow up testing" above). HPV testing is preferred because it is as effective as Pap smear but requires fewer visits and less need for colposcopy. Treatment to remove or destroy the abnormal cells (See "Patient information: Treatment of abnormal Pap smears"). Repeat colposcopy and Pap smear at 12 months.

Since many of these lesions will heal without treatment, some women prefer to delay treatment and have close monitoring. Treatment is the best option if LSIL persists, if the woman would have difficulty remembering to follow-up every six months, if the lesion is large (large lesions usually persist), if the lesion extends into the inner cervix (where it is difficult to see), or if the patient prefers treatment.

HIGH-GRADE SQUAMOUS LESION (HSIL) — These are moderate to severe changes in the cells of the cervix that may be precancerous (show picture 1). Approximately 20 percent of women will develop cervical cancer over a period of several years if no treatment is given.

A number of terms are used to describe high grade lesions, including CIN 2 and 3, moderate and severe dysplasia, and carcinoma in situ (CIS).

Follow up of HSIL — All women with high-grade lesions (HSIL) should have a colposcopy and biopsy. If colposcopy does not detect a high grade abnormality, close follow-up, further testing, and/or treatment may be recommended.

Treatment of HSIL — Women with high grade abnormalities should be treated because approximately 20 percent of untreated abnormalities will develop into invasive cancer. The most common treatment involves removal (excision) of the abnormal area of the cervix. (See "Patient information: Treatment of abnormal Pap smears").

Adolescent patients may be able to delay treatment of HSIL because, in this age group, there is a good chance that the abnormal area will heal without treatment. Close follow up is required, including colposcopy and Pap smear every four to six months. To delay treatment, the provider must be able to see the entire cervix during colposcopy and a test of the inner cervix (called endocervical curettage) must be negative.

Likewise, for pregnant women with HSIL, treatment is often delayed until after delivery. Colposcopy and Pap smear are generally performed several times during the pregnancy.

SQUAMOUS CELL CARCINOMA — Squamous cell carcinoma is the medical term for cervical cancer. Women with this result require a biopsy, which is usually performed with colposcopy. If biopsy confirms that cancerous cells are present, treatment is strongly recommended. The diagnosis and treatment of early stage cervical cancer is discussed in a separate topic review. (See "Patient information: Treatment of early stage cervical cancer").

GLANDULAR CELL ABNORMALITIES — Glandular cells develop from the inside the cervix (called the endocervical canal). Glandular cells can also come from the endometrium (lining of the uterus), the fallopian tube, or the ovary. Women with abnormal glandular cells need to have further testing to determine the source of the abnormality, if cancer or precancer is present, and to determine if treatment is needed.

Follow up testing — All women with atypical glandular cells (AGC) require further testing (colposcopy, biopsy, endometrial biopsy). This is because 10 to 40 percent of women with atypical glandular cells have precancerous or cancerous cells when evaluated by colposcopy and biopsy.

Treatment — Treatment of AGC depends upon the underlying abnormality and may involve monitoring, removal of a large part of the inner cervix, or less commonly, hysterectomy. (See "Patient information: Treatment of abnormal Pap smears").

PREVENTING CERVICAL CANCER

HPV vaccine — A vaccine (Gardasil®) is now available to help prevent infection with some types of HPV (types 6, 11, 16, and 18). Approximately 70 percent of cervical cancers result from infection with HPV 16 and 18, and approximately 90 percent of cases of genital warts result from infection with HPV 6 and 11. The vaccine was proven to be safe and effective in several large clinical trials [1,2].

The vaccine is currently recommended for all females who are between ages 9 and 26 years. Decisions about the age at which to start HPV immunization have been guided by the age at which the greatest number of women is infected with HPV and estimates regarding how long the vaccine continues to prevent infection. While it is not known exactly how long the vaccine protects against HPV infection, clinical trials prove protection for at least four years [3]. Further study is underway to determine if a booster shot is needed after this time.

The vaccine has not been studied in women over 26 years old and thus its effectiveness is uncertain. Women over this age are more likely to have been exposed to the four types of HPV in the vaccine (6, 11, 16, and 18); the vaccine does not protect against HPV infection if the woman has previously been exposed.

The vaccine is given by injection and requires three doses; the first injection is followed by a second and third dose two and six months later.

It is not known if vaccination of men could help to reduce the incidence of cervical cancer in women. Studies are currently underway to address this question. The vaccine is not currently recommended during pregnancy.

Sexual contact — Avoiding sex or sexual contact is not a practical way to prevent infection with HPV. Condoms provide partial protection, but not complete protection because they do not cover all areas of the genitals. Having a limited number of sexual partners may reduce the risk of HPV infection.

Smoking cessation — Women who smoke cigarettes are at increased risk of developing cervical cancer [4]. Cigarette smoking and HPV infection increase the risk of developing high-grade squamous lesions. The risk of cervical cancer is increased two- to four-fold among cigarette smokers compared to nonsmokers.

Women who smoke and have an abnormal Pap smear can reduce their risk of cervical cancer by quitting smoking. (See "Patient information: Smoking cessation").

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute

(www.nci.nih.gov)
American Society of Cytopathology

(www.cytopathology.org)
American Society for Colposcopy and Cervical Pathology

(www.asccp.org)
American Cancer Society

(www.cancer.org, search for HPV)
National HPV and Cervical Cancer Public Education Campaign

Telephone: 1-866-280-6605
(www.cervicalcancercampaign.org)
National Institute of Allergy and Infectious Diseases

(www.niaid.nih.gov/factsheets/stdhpv.htm)
Center for Disease Control and Prevention

(www.cdc.gov/)
American Social Health Association

(http://www.ashastd.org/)


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