HPV and Pap Testing
What causes cervical cancer?
Nearly all cases of cervical cancer are caused by infection with sexually transmitted oncogenic, or high-risk, types of human papillomavirus, or HPV. There are about a dozen high-risk HPV types, and just two of these, HPV types 16 and 18, are responsible for about 70% of all cervical cancers. Infections with high-risk HPV types also cause most anal cancers; many vaginal, vulvar, and oropharyngeal cancers; and some penile cancers.
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. These transient infections may cause temporary changes in cervical cells. If a cervical infection with a high-risk HPV type persists, the cellular changes can eventually develop into precancerous lesions. If precancerous lesions are not treated, they can progress to cancer. It can take 10 to 20 years or more for a persistent infection with a high-risk HPV type to develop into cancer.
What is cervical cancer screening?
Cervical cancer screening is an essential part of a woman’s routine health care. 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.
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:
- 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. 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 screen, chances are good that those changes will be detected at the next screening exam, 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 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 and 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, lengthening the screening interval to 5 years still allows abnormalities to be detected in time to treat them while also 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 can also detect HPV16 and HPV18—the types that cause most cervical cancers—specifically, and sometimes findings for these specific types are reported.
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 (non-neoplastic) findings, such as common infections or inflammation. Pap test results also indicate whether the specimen was satisfactory or unsatisfactory for examination. Guidelines committees are reevaluating how results of cervical screening tests are reported, based on the most up-to-date research on HPV natural history.
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, since some abnormalities, especially more minor ones, will go away on their own as the immune system controls the HPV infection. If she has more severe cell changes and/or evidence of HPV16 or HPV18, she may be recommended to have a colposcopy, a procedure that involves the use of an instrument much like a microscope (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.
For a woman receiving HPV testing alone:
HPV-alone testing, also called primary HPV testing, looks for DNA from HPV types 16 and 18 specifically, as well as from 12 other high-risk HPV types. If a woman who is having primary HPV testing is positive for HPV types 16 or 18, she will be referred to colposcopy immediately. A woman who tests negative for HPV types 16 and 18 but positive for any of the other high-risk HPV types will generally have a Pap test. If the Pap test results are normal, she will undergo repeat testing after a year; otherwise, she will have a colposcopy.
For a woman receiving Pap and HPV cotesting:
If a woman is found to have a normal Pap test result with a positive result on an HPV test that detects any high-risk HPV type, the provider will usually have her return in a year to see if the HPV infection persists and whether any cell changes have developed that need follow-up testing. If a woman is still HPV positive after 1 year, she will generally be referred for colposcopy. If a woman tests positive for HPV16 or 18 specifically, she will be referred to colposcopy immediately.
If a woman is found to have an abnormal Pap test result with a negative HPV test, the provider may have the woman return in a year for repeat screening. In rare cases (e.g., if she is found to have ASC-H or HSIL), a woman would be referred to colposcopy immediately.
If a woman is found to have an abnormal Pap test result with a positive HPV test that detects any high-risk HPV type, the doctor will usually have the woman receive immediate follow-up testing with colposcopy.
For a woman receiving Pap testing alone:
If a woman who is receiving Pap testing alone is found to have minor abnormal cell changes (ASC-US), her health care provider may have the sample tested for high-risk HPV types or may repeat the Pap test in 12 months. Many times, such changes go away without treatment, especially if there is no evidence of infection with high-risk HPV. Providers may prescribe estrogen cream for women with abnormal cell changes who are near or past menopause. Because low hormone levels can cause cell changes, applying an estrogen cream to the cervix for a few weeks can usually help to clarify their cause.
If a woman with ASC-US is found to have high-risk HPV, she will generally have immediate colposcopy.
If a woman has LSIL results on a Pap test, she will have a repeat Pap test in 12 months or immediate colposcopy, depending on her age and whether she tests positive for high-risk HPV.
Follow-up testing for all other abnormal Pap results will typically involve a colposcopy.
As of early 2019, guidelines for the management of women with abnormal screening results are being updated by a group of clinical societies.
How are cervical abnormalities treated?
If biopsy analysis of cells from the affected area of the cervix shows precancerous lesions, further treatment is probably needed, depending on a woman’s age, pregnancy status, and future fertility concerns. Without treatment, these cells may turn into cancer.
The most common method used to treat precancerous cervical lesions is the loop electrosurgical excision procedure (LEEP), in which an electrical current that is passed through a thin wire loop acts as a knife to remove tissue. Less commonly used methods to treat such lesions include cryotherapy, laser therapy, and conization.
The screening guidelines call for women who have been treated for precancerous lesions or cancer to continue screening for at least 20 years, even if they are over 65.
Do women who have been vaccinated against HPV still need to be screened for cervical cancer?
Yes. Because current HPV vaccines do not protect against all HPV types that cause cervical cancer, it is important for vaccinated women to continue to undergo routine cervical cancer screening.
What research is being done to improve cervical cancer screening?
Several new tests are currently in development that can improve the evaluation of HPV-positive women. One test that is undergoing regulatory evaluation but is not yet clinically available is based on detection of two proteins that indicate an active HPV infection—p16 and Ki-67. P16/Ki-67 dual staining was found to be more accurate than Pap testing (the current standard for follow-up testing of HPV-positive women) at predicting whether an HPV-positive woman would go on to develop cervical precancer within 5 years. If positive for p16/Ki-67, she may be referred for colposcopy and biopsy.
Researchers at the NCI have developed an artificial intelligence approach called automated visual evaluation (AVE) that can analyze digital images of a woman’s cervix and accurately identify precancerous changes that require medical attention. The images can be taken with a cell phone or similar device outfitted with a camera, making this approach potentially useful for cervical screening in low-resource settings.
Another improvement that may be of particular importance where healthcare resources are limited is the ability to do self-sampling. A clinical study conducted among more than 180,000 women in the Netherlands found that HPV testing done on cervical samples collected by women themselves had similar accuracy to that of clinician-collected samples for the detection of moderately to severely abnormal cervical cells. These findings suggest that self-sampling has the potential be used as a primary screening method in routine cervical screening.