Cervical cancer is nearly always caused by infection with human papillomavirus (HPV).
Cervical cancer is a disease in which malignant (cancer) cells form in the cervix. The cervix is the lower, narrow end of the uterus (the hollow, pear-shaped organ where a fetus grows). The cervix connects the uterus to the vagina (birth canal). Cervical cancer usually develops slowly over time. Before cancer appears in the cervix, the cells of the cervix go through a series of changes in which cells that are not normal begin to appear in the cervical tissue.
When cells change from being normal cells to abnormal cells, it is called dysplasia. The abnormal cervical cells may go away without treatment, stay the same, or turn into cancer cells over many years.
The Importance of Cervical Cancer Screening
What is cervical cancer screening?
Cervical cancer screening is an essential part of a woman’s routine health care. Nearly all cases of cervical cancer are caused by infection with sexually transmitted oncogenic, or high-risk, types of human papillomavirus, or HPV. The primary goal of screening is to identify precancerous lesions caused by HPV so they can be removed to prevent invasive cancers from developing.
A secondary goal is to find cervical cancers at an early stage when they can usually be treated successfully. Routine cervical screening has been shown to greatly reduce both the number of cervical cancer cases and deaths from the disease.
For many years, cytology-based screening, known as the Pap test or Pap smear, was the only method of screening. Its use reduced cervical cancer incidence and deaths in countries where screening is common.
However, with the advent of the ability to test for HPV, cervical cancer screening now includes three approaches: HPV testing, which looks for the presence of high-risk HPV types in cervical cells; Pap testing; and HPV/Pap cotesting, which checks the same cell sample for both high-risk HPV types and cervical cell changes.
How is cervical cancer screening done?
Cervical cancer screening can be done in a medical office, a clinic, or a community health center. It is often done during a pelvic examination.
While a woman lies on an exam table, a health care professional inserts an instrument called a speculum into her vagina to widen it so that the upper portion of the vagina and the cervix can be seen. This procedure also allows the health care professional to take a sample of cervical cells. The cells are taken with a wooden or plastic scraper and/or a cervical brush and placed in a vial of liquid preservative.
The slide or vial is then sent to a laboratory where the cells are tested for the presence of high-risk types of HPV and/or examined under a microscope with an automated liquid-based Pap cytology test. When both tests are done using the same sample, this is referred to as “cotesting.”
Researchers have found that screening may be less effective for obese women, possibly because of challenges in visualizing the cervix and obtaining a cell sample. Approaches to improve cervical visualization in obese women, including the use of larger speculum, may be helpful.
When should a woman begin cervical cancer screening, and how often should she be screened?
Women should talk with their doctor about when to start screening and how often to be screened. In August 2018, updated screening guidelines were released by the United States Preventive Services Task Force. The updated guidelines are as follows:
- Women ages 21 through 29 should be screened with a Pap test every 3 years
- Women ages 30 through 65 should be screened with any of three tests:
- every 5 years with high-risk HPV testing alone
- every 5 years with Pap and high-risk HPV cotesting
- every 3 years with a Pap test alone
- Women with certain risk factors may need to have more frequent screening or to continue screening beyond age 65. These risk factors include:
- being infected with the human immunodeficiency virus (HIV)
- being immunosuppressed
- having been exposed to diethylstilbestrol before birth
- having been treated for a precancerous cervical lesion or cervical cancer
- Screening for cervical cancer is not recommended for:
- women younger than 21 years
- women older than 65 years who have had adequate prior screening, with normal results, and who are not otherwise at high risk for cervical cancer
- women who have had a total hysterectomy (surgery to remove the uterus and cervix) and have no history of high-grade cervical lesions or cervical cancer
A joint statement released by the American College of Obstetricians and Gynecologists, American Society for Colposcopy and Cervical Pathology, and the Society of Gynecologic Oncology noted that the updated guidelines are largely in line with their clinical guidance, with some differences in the details.
The screening intervals in the 2018 guidelines reflect scientists’ evolving understanding of the natural history of HPV infection and cervical cancer. Although HPV infection of the cervix is very common, most infections will be controlled by the immune system over the course of 1 to 2 years. Because most HPV infections are transient and produce only temporary changes in cervical cells, overly frequent screening could detect HPV infections or cell changes that would never cause cancer.
Treating abnormalities that would have gone away on their own can cause needless psychological stress. Follow-up tests and treatments can also be uncomfortable, and the removal of cervical tissue has the potential to weaken the cervix and may affect fertility or slightly increase the rate of premature delivery, depending on how much tissue is removed.
These screening intervals also limit false-negative results that would delay the diagnosis and treatment of a precancerous condition or cancer. With these intervals, if an HPV infection or cell changes are missed at one screening exam, chances are good that those changes will be detected at the next one, when they can still be treated successfully.
The success of cervical cancer screening is due, in part, to the repeat testing that women typically undergo over many years. A study of a large population of women receiving routine screening showed that women with a history of negative HPV/Pap cotest results have a very low risk of developing precancer or cancer even if a subsequent screening test reveals a new HPV infection or abnormal cervical cells.
How do the three testing options compare?
For women age 30 or older, both HPV/Pap cotesting and HPV testing alone are more sensitive than Pap testing alone. Therefore, a woman with a negative HPV test and normal Pap test—or just a negative HPV test—has a very low risk of developing precancerous cervical lesions over the next several years.
It is for that reason that, when Pap and HPV cotesting or HPV testing alone are used, the recommended screening interval is 5 years: this longer interval (compared with 3 years for women receiving Pap testing alone) still allows abnormalities to be detected in time to treat them while reducing the detection of HPV infections that would be successfully controlled by the immune system.
Both Pap and HPV cotesting and HPV testing alone may also improve the detection of glandular cell abnormalities, including adenocarcinoma of the cervix (cancer of the glandular cells of the cervix). Glandular cells are mucus-producing cells found in the endocervical canal (the opening in the center of the cervix) or in the lining of the uterus. Glandular cell abnormalities and adenocarcinoma of the cervix are less common than squamous cell abnormalities and squamous cell carcinoma. Pap testing is not as good at detecting adenocarcinoma and glandular cell abnormalities as it is at detecting squamous cell abnormalities and cancers.
What do the results of cervical cancer screening tests mean?
A health care provider may simply describe Pap test results to a patient as “normal” or “abnormal.”
Likewise, HPV test results can either be “positive,” meaning that a patient’s cervical cells are infected with one or more of a group of high-risk HPV types (which is what most commercially available HPV tests detect), or “negative,” indicating that none of the high-risk HPV types were found. Several HPV tests are specific for HPV16 and HPV18—the types that cause most cervical cancers.
A woman may want to ask her provider for specific information about her Pap and HPV test results and what these results mean.
Most laboratories in the United States use a standard set of terms, called the Bethesda System, to report Pap test results. Under the Bethesda System, samples that have no cell abnormalities are reported as “negative for intraepithelial lesion or malignancy.” A negative Pap test report may also note certain benign findings, such as common infections or inflammation. Pap test results also indicate whether the specimen was satisfactory or unsatisfactory for examination. Guidelines committees are re-evaluating how results of cervical screening tests are reported, based on the most up-to-date research on the natural history of HPV infections.
The Bethesda System considers abnormalities of squamous cells and glandular cells separately. Squamous cell abnormalities are divided into the following categories, ranging from the mildest to the most severe.
- Atypical squamous cells (ASC) are the most common abnormal finding in Pap tests. The Bethesda System divides this category into two groups, ASC-US and ASC-H:
- ASC-US: atypical squamous cells of undetermined significance. The cells do not appear completely normal, but the cause is unclear. The changes may be related to an HPV infection, but they can also be caused by other factors.
- ASC-H: atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion. ASC-H lesions may be at higher risk of being precancerous than ASC-US lesions.
- Low-grade squamous intraepithelial lesions (LSILs) are considered mild abnormalities caused by HPV infection. LSILs often return to normal as the immune system controls the infection, especially in younger women.
- High-grade squamous intraepithelial lesions (HSILs) are more severe abnormalities that have a higher likelihood of progressing to cancer if left untreated.
- Carcinoma in situ (CIS) refers to severely abnormal cells that resemble cancer cells but remain on the surface of the cervix and have not invaded more deeply or spread beyond the cervix.
- Squamous cell carcinoma is cervical cancer. The abnormal squamous cells have invaded more deeply into the cervix or into other tissues or organs. In a well-screened population, such as that in the United States, a finding of cancer during cervical screening is extremely rare.
Glandular cell abnormalities describe abnormal changes that occur in the glandular tissues of the cervix. The Bethesda system divides these abnormalities into the following categories:
- Atypical glandular cells (AGC), meaning the glandular cells do not appear normal, but doctors are uncertain about what the cell changes mean.
- Endocervical adenocarcinoma in situ (AIS), meaning that severely abnormal cells are found but have not spread beyond the glandular tissue of the cervix.
- Adenocarcinoma includes not only cancer of the endocervical canal itself but also, in some cases, endometrial, extrauterine, and other cancers.
What follow-up tests are done if cervical cancer screening results are abnormal?
Depending on the test results, a woman may be recommended to have repeat screening in a year because some abnormalities, especially more minor ones (ASC-US), will go away on their own as the immune system controls the HPV infection. If a woman has more severe cell changes (ASC-H or HSIL) and/or evidence of HPV16 or HPV18, she may be recommended to have a colposcopy, a procedure that involves the use of an instrument (called a colposcope) to examine the cervix.
During a colposcopy, the provider inserts a speculum into the vagina to widen it and may apply a dilute vinegar solution to the cervix, which causes areas of HPV infection, inflammation, precancer, or other cell changes to turn white. The provider then uses the colposcope (which remains outside the body) to examine the cervix. When a provider performs colposcopy, he or she will usually remove cells or tissues from one or more concerning areas for examination under a microscope, a procedure called a biopsy.
Can an HPV infection come back after a negative test?
Yes. Sometimes, after many years of negative HPV tests, an infection that the immune system had previously controlled can become active again, resulting in an HPV-positive test result. Such reactivation of an old, previously undetectable HPV infection can happen due to age-related changes in the immune system.
There is no way to tell whether a newly positive HPV result is a sign of a new infection or represents a reactivation of an old infection. It is also not yet known whether reactivated HPV infections can cause cell changes that lead to precancer and cancer.
Do women who have been vaccinated against HPV still need to be screened for cervical cancer?
Yes. Current HPV vaccines do not protect against all HPV types that cause cervical cancer, so it is important for vaccinated women to continue to undergo routine cervical cancer screening.
Cervical Cancer Prevention
Key Points
- Avoiding risk factors and increasing protective factors may help prevent cancer.
- The following are risk factors for cervical cancer:
- HPV infection
- DES
- In women who are infected with HPV, other risk factors add to the increased risk of cervical cancer:
- Giving birth to many children
- Using oral contraceptives for a long time
- Smoking cigarettes
- The following increase the risk of HPV infection:
- Having a weakened immune system
- Being sexually active at a young age or having many sexual partners
- The following protective factors decrease the risk of cervical cancer:
- Avoiding sexual activity
- Getting an HPV vaccine
- Using barrier protection during sexual activity
- Cancer prevention clinical trials are used to study ways to prevent cancer.
- New ways to prevent cervical cancer are being studied in clinical trials.
Avoiding risk factors and increasing protective factors may help prevent cancer.
Avoiding cancer risk factors may help prevent certain cancers. Risk factors include smoking, being overweight, and not getting enough exercise. Increasing protective factors such as quitting smoking and exercising may also help prevent some cancers. Talk to your doctor or other health care professional about how you might lower your risk of cancer.
The following are risk factors for cervical cancer:
HPV infection
Cervical cancer is almost always caused by human papillomavirus (HPV) infection that is spread through sexual contact. There are more than 80 types of human papillomavirus and about 30 of these can infect the cervix. HPV types 16 and 18 are most often linked to cervical cancer.
Most of the time, the body’s immune system can fight the HPV infection before cancer forms. Only a very small number of women infected with HPV develop cervical cancer.
DES
Being exposed to a drug called diethylstilbestrol (DES) while in the mother’s womb increases the risk of cervical dysplasia and clear cell adenocarcinoma of the vagina and cervix. Between 1940 and 1971, DES was given to some pregnant women in the United States to prevent miscarriage (premature birth of a fetus that cannot survive) and premature labor.
In women who are infected with HPV, other risk factors add to the increased risk of cervical cancer:
Giving birth to many children
Among women who are infected with HPV, those who have had 7 or more full-term pregnancies have an increased risk of cervical cancer.
Using oral contraceptives for a long time
Among women who are infected with HPV, those who have used oral contraceptives (“the Pill”) for 5 to 9 years have a risk of cervical cancer that is 3 times greater than that of women who have never used oral contraceptives. The risk is 4 times greater after 10 or more years of use. In women who stop taking oral contraceptives, over a 10 year period, the risk of cervical cancer returns to that of women who never used oral contraceptives.
Smoking cigarettes
Among women who are infected with HPV, those who either smoke cigarettes or breathe in secondhand smoke have an increased risk of cervical cancer. The risk increases with the number of cigarettes smoked per day and how long the woman has smoked. Current and former smokers have 2 to 3 times the risk of cervical dysplasia and invasive cervical cancer.
The following increase the risk of HPV infection:
Having a weakened immune system
Having a weakened immune system caused by immunosuppression increases the risk of HPV infection and cervical cancer. Immunosuppression weakens the body’s ability to fight infection and other diseases.
Immunosuppression can be caused by these and other conditions:
- Human immunodeficiency virus (HIV). This virus causes AIDS and weakens the body’s immune system.
- Medicine given to prevent organ rejection after transplant. Women who have an organ transplant are given medicine to weaken the body’s immune system and help prevent organ rejection.
Women who are infected with the HIV virus or who take medicine to prevent organ rejection after transplant are less able to fight HPV infection and are at increased risk of cervical cancer.
Being sexually active at a young age or having many sexual partners
The risk of HPV infection is higher in women who become sexually active before age 18 and in women who have had 6 or more sexual partners.
The following protective factors decrease the risk of cervical cancer:
Note: Screening with the Pap test and the HPV DNA test reduces the number of new cases of cervical cancer.
Avoiding sexual activity
Nearly all cases of cervical cancer are caused by HPV infection, which is spread through sexual activity. Women who are not sexually active have almost no risk of cervical cancer.
Getting an HPV vaccine
Vaccines that protect against HPV infection greatly reduce the risk of cervical cancer. These vaccines do not protect women who are already infected with HPV.
Several HPV vaccines have been approved by the U.S. Food and Drug Administration (FDA). These vaccines have been shown to prevent infection with the types of HPV that cause most cervical cancers. Protection against HPV infection lasts for 6 to 8 years. It is not known if the protection lasts longer.
Harms of HPV vaccines include dizziness, feeling faint, headache, fever, and redness, tenderness, or warmth at the place of injection. Allergic reactions are rare. Getting the HPV vaccine while pregnant does not have a harmful effect on the pregnancy.
Using barrier protection during sexual activity
Some methods used to prevent sexually transmitted diseases (STDs) decrease the risk of HPV infection. The use of a barrier method of birth control, such as a condom or diaphragm, helps protect against HPV infection.
Drugs approved for Cervical Cancer
Drugs Approved to Prevent Cervical Cancer
- Cervarix (Recombinant HPV Bivalent Vaccine)
- Gardasil (Recombinant HPV Quadrivalent Vaccine)
- Gardasil 9 (Recombinant HPV Nonavalent Vaccine)
- Recombinant Human Papillomavirus (HPV) Bivalent Vaccine
- Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine
- Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine
Drugs Approved to Treat Cervical Cancer
- Avastin (Bevacizumab)
- Bevacizumab
- Bleomycin Sulfate
- Hycamtin (Topotecan Hydrochloride)
- Keytruda (Pembrolizumab)
- Mvasi (Bevacizumab)
- Pembrolizumab
- Topotecan Hydrochloride
Drug Combinations Used in Cervical Cancer
- Gemcitabine-Cisplatin
