Overview

Information about the prevention of cancer and the science of screening appropriate individuals at high-risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best “treatment” of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable. Each year in the United States, there are an estimated 9710 new cases of cervical cancer and 3700 deaths due to the disease.[1] Widespread use of a screening test called the Pap smear has led to a decline in the number of deaths resulting from cervical cancer. Continued progress and education about screening may allow for earlier detection and higher cure rates.

The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person´s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (i.e. the correlation between smoking and lung cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer.

  • Hereditary or Genetic Factors
  • Environmental or Non-Genetic Factors
    • HPV infection
    • Chlamydia
    • HIV
    • Cigarette smoking
    • Reproductive factors
  • Prevention
    • HPV vaccine
    • Condom use
    • Detection and treatment of precancerous changes to the cervix
  • Screening and Early Detection
    • Pap smear
    • HPV testing
  • Strategies to Improve Screening and Detection

Heredity or Genetic Factors

At this time, researchers have not identified any genetic factors that contribute to the development of cervical cancer.

Environmental or Non-Genetic Factors

HPV infection: The most important cause of cervical cancer is infection with a high-risk type of human papillomavirus (HPV). Human papillomaviruses consist of a group of more than 100 different viruses.[2] Some types of HPV cause warts on the hands or feet; others cause genital warts; and some have been linked with cancer, most notably cervical cancer. The types of HPV most commonly linked with cervical cancer are HPV 16 and HPV 18, but several other high-risk types contribute to cancer as well.

The types of HPV that cause cervical cancer or genital warts are transmitted sexually. HPV infection is extremely common and generally occurs soon after an individual becomes sexually active. Although most infections resolve on their own, some persist and can lead to precancerous or cancerous changes to the cervix, vulva, vagina, penis, and anus. Persistent infections appear to pose the greatest cancer threat.

Chlamydia:   Chlamydia trachomatis is another common sexually transmitted infection, and is frequently reported among women with cervical cancer. To clarify the role of chlamydia in cervical cancer, researchers in Sweden conducted a study to determine whether women with a history of chlamydia were more likely to have persistent HPV infections than women without a history of chlamydia.[3] The researchers found that women who reported a history of chlamydia were roughly twice as likely to have persistent HPV as women without a history of chlamydia. Women who reported using condoms were less likely to have persistent HPV.

Human Immunodeficiency Virus (HIV):   Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are both associated with the development of acquired immunodeficiency syndrome (AIDS). Infection with HIV-1 or HIV-2 may contribute to the development of cervical cancer by suppressing the immune system.

Cigarette smoking: Cigarette smoking is consistently linked with an increased risk of developing cervical cancer. A recent study suggests that the link between smoking and cervical cancer may be explained at least in part by increased persistence of high-risk HPV infections in women who smoke.[4]

Reproductive factors: Among women infected with HPV, risk of cervical cancer appears to be increased among women who have had a greater number of full-term pregnancies or a longer duration of oral contraceptive use.[5]

Prevention

Important approaches to the prevention of cervical cancer include prevention of HPV infection, as well as detection and treatment of precancerous changes to the cervix.

HPV vaccine: The development of vaccines that prevent infection with two high-risk types of HPV (HPV 16 and HPV 18) has heralded the start of a new era in cervical cancer prevention. Because HPV types 16 and 18 are thought to account for roughly 70 percent of all cases of cervical cancer,[2] widespread use an HPV vaccine has the potential to eliminate most (but not all) cases of cervical cancer and precancerous changes to the cervix. One of the vaccines – Gardasil® – also prevents infection with HPV types 6 and 11, which cause a majority of cases of genital warts. It is important to note that these vaccines are intended to prevent infection with HPV and not to treat existing infections or cervical cancer. Because infection with HPV is extremely common and generally occurs soon after an individual becomes sexually active, vaccination is likely to have the greatest effect when administered before the teen years.

Condom use: Because vaccination does not protect against all high-risk types of HPV, supplementing use of the vaccine with other approaches to HPV prevention will be important. Results from a study conducted among female college students suggest that consistent use of condoms reduces the likelihood of developing an HPV infection. During the year after first sexual intercourse, 37% of women became infected with HPV. Compared to women whose partners used condoms less than 5% of the time, women whose partners used condoms 100% of the time were 70% less likely to become infected with HPV, and women whose partners used condoms more than half of the time (but less than 100% of the time) were 50% less likely to become infected with HPV.[6]

Detection and Treatment of Precancerous Changes to the Cervix: Cervical cancer is generally preceded by precancerous changes to the cervix. Detection and treatment of these precancerous changes can prevent the development of cancer. The best way to identify precancerous cervical changes is through cervical cancer screening. Screening is discussed in the section below.

Screening and Early Detection

For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer. When individuals are at high risk for a type of cancer, this means that they have certain characteristics or exposures, called risk factors that make them more likely to develop that type of cancer than those who do not have these risk factors. The risk factors are different for different types of cancer. An awareness of these risk factors is important because 1) some risk factors can be changed (such as smoking or dietary intake), thus decreasing the risk for developing the associated cancer; and 2) persons who are at high risk for developing a cancer can often undergo regular screening measures that are recommended for that cancer type. Researchers continue to study which characteristics or exposures are associated with an increased risk for various cancers, allowing for the use of more effective prevention, early detection, and treatment strategies.

Women are advised to begin cervical cancer screening within three years of becoming sexually active, and no later than the age of 21.[7] Screening generally includes a Pap test, and may also include an HPV test. Regular surveillance can increase the possibility that cancer could be found at an early stage when treatment is most likely to produce a cure.

Papanicolaou (Pap) Smear: Routine screening with a Pap smear is used to detect cancerous cells in the cervix early, as well as to detect abnormal cells in the cervix before they become cancerous. During a Pap smear, a sample of cells from the cervix is taken with a small wooden spatula or brush and examined under the microscope.

In place of the conventional Pap test, many women will be tested using a newer type of Pap test that uses a method known as liquid-based cytology. With this method, cervical material that is removed by spatula or brush is rinsed in liquid. The liquid is then processed to isolate the cells that need to be analyzed. These cells are spread in a thin layer on a slide and viewed under a microscope. This technique may reduce the number of samples that are classified as “unsatisfactory” (unable to be reviewed because of poor sample quality), but it’s still uncertain whether this method is superior to the conventional Pap test.[8]

The results of the Pap test are generally classified into the following categories: negative (normal); atypical squamous cells of undetermined significance (ASC-US); atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H); atypical glandular cells (AGC); adenocarcinoma in situ (AIS); low-grade squamous intraepithelial lesions (LSIL; includes mild dysplasia); high-grade squamous intraepithelial lesions (HSIL; includes moderate or severe dysplasia and carcinoma in situ); or cancer.[9]

If the results are normal, no further evaluation is recommended. Women who have normal results will simply need to continue being screened on the schedule recommended by their doctor.

Abnormal results from a Pap smear do not necessarily indicate cancer. Other conditions such as inflammation and sexually transmitted diseases can cause abnormal changes in cells.

If the Pap test results indicate ASC-US – a finding of uncertain significance – follow-up may involve HPV testing, repeated Pap testing, or colposcopy.[10] For women who undergo HPV testing, an ASC-US result coupled with a negative HPV test may indicate that a woman can simply resume usual cervical cancer screening. An ASC-US result coupled with a positive HPV test may suggest a need for additional follow-up. HPV testing is discussed further in the section below.

Women with a Pap test indicating other cervical abnormalities (ASC-H, AGC, LSIL, or HSIL) often undergo a colposcopy for further evaluation.[10] During a colposcopy, a physician uses a microscope called a colposcope to better see the cervix. The physician applies a mild vinegar solution to the cervix, which makes abnormal cells appear more white than pink. If abnormal areas are identified, the physician may remove samples of tissue so that the cells can be further evaluated—a procedure called a biopsy.

The results of a biopsy allow the physician to diagnose cancer or precancerous conditions. Precancerous changes to the cervix are called cervical intraepithelial neoplasia (CIN). The severity of CIN is graded on a scale of 1 to 3, with 3 being the most severe. CIN2 and CIN3 are considered “high-grade” CIN and may progress to cancer if not treated.

In addition to colposcopy and cervical biopsy, follow-up of abnormal Pap test results may also involve one or more of the following procedures:

  • Endocervical Curettage: This procedure may be performed at the same time as the punch biopsy, especially if there is concern that there may be abnormal tissue past the opening of the cervix that cannot be seen with the colposcope. During an endocervical curettage, a small spoon-shaped instrument called a curette is used to scrape cells away from inside the endocervical canal. These cells are then sent to the lab for examination under a microscope.
  • Conization: If the information obtained from colposcopy, biopsy and/or curettage is inconclusive, a physician might perform a conization. During a conization, or cone biopsy, the physician removes a cone-shaped sample of tissue from the cervical canal. The sample is then sent to the lab for examination. Conization can also serve as the primary treatment of precancerous cervical cancer, as a large sample is removed and can sometimes remove any cancerous tissue in the process. This is a fairly intrusive procedure and can involve significant complications.
  • Loop Electrosurgical Excision Procedure (LEEP): Loop electrosurgical excision procedure (LEEP), also called large loop excision of the transformation zone (LLETZ), is simpler and less invasive than conization. During LEEP, a physician applies a local anesthetic to the cervix and then inserts a wire loop into the vagina. A high frequency electrical current is run through the wire to remove abnormal tissue from both the cervix and the endocervical canal. Like conization, LEEP can be used not only as a diagnostic tool, but also as treatment, as large and deep sections of abnormal tissue can be removed.
  • Endometrial biopsy: An endometrial biopsy refers to the removal of a tissue sample from the lining of the uterus (the endometrium). Endometrial biopsy may be performed in some women whose Pap test indicates atypical glandular cells10

HPV Testing – Hybrid Capture® 2: The recognition that specific types of HPV can cause cervical cancer led to the development of a test to identify women infected with high-risk types of HPV. The Hybrid Capture® 2 test detects 13 high-risk types of HPV. Information about HPV status may guide decisions about follow-up care.

An important use for HPV testing is further evaluation of women with an indeterminate Pap test result (atypical squamous cells of uncertain significance, or ASC-US). Women with ASC-US who test positive for high-risk HPV may undergo an immediate colposcopy, whereas women who test negative for high-risk HPV may simply be rescreened at a later time. This use of HPV testing is appropriate for women of all ages.[10]

HPV testing may also have a role in initial cervical cancer screening, but conclusive evidence about this is still lacking. In the meantime, some organizations have supported the combination of HPV testing and Pap testing for screening women over the age of 30. Women who test negative for both tests may need not be rescreened for up to three years.[11] Currently, the combination of HPV testing and Pap testing is not recommended for screening younger women because most will have HPV infections that will clear without causing precancerous cervical lesions.

Strategies to Improve Screening and Prevention

The development of more effective strategies for prevention and early detection requires that new and innovative approaches be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new strategies. Future progress in the prevention and early detection of cervical cancer will result from the continued evaluation of new strategies in clinical trials.

Patients may gain access to better approaches to prevention or early detection by participating in a clinical trial. Participation in a clinical trial also contributes the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the prevention and early detection of cervical cancer include the following:

Therapeutic vaccines: In contrast to vaccines such as Gardasil™ and Cervarix™, which are intended to prevent infection with specific types of HPV, therapeutic vaccines would treat the infection, precancerous cervical changes, or cancer in individuals who are already infected with HPV. Thus far, therapeutic vaccines have proven to be more challenging to develop than preventive vaccines.

Single-type HPV tests: In addition to the Hybrid Capture™ 2 test, which tests for infection with any of 13 high-risk types of HPV, there may also be a benefit to identifying the specific type of high-risk HPV that is present. A study published in the Journal of the National Cancer Institute first tested women with the Hybrid Capture 2 test.[12] Those who tested positive were then tested specifically for HPV16 and HPV18.   Over the next 10 years, 17 percent of the women with HPV16 developed cervical precancer or cancer, as did 14 percent of the women with HPV18. Women who tested positive to the Hybrid Capture 2 test but negative for HPV16 and HPV18 had a much lower risk; three percent developed cervical precancer or cancer during the 10 years of follow-up. Among women who were negative to the Hybrid Capture 2 test, less than 1 percent developed cervical precancer or cancer. These results suggest that the addition of single-type HPV testing may allow for more accurate estimation of a woman’s risk of precancer or cancer.

References

[1] American Cancer Society. Cancer Facts & Figures 2006. Available at: http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf (Accessed August 29, 2006).

[2] National Cancer Institute Fact Sheet. Human Papillomaviruses and Cancer: Questions and Answers. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/HPV (Accessed September 11, 2006).

[3] Silins I, Ryd W, Strand A et al. Chlamydia trachomatis infection and persistence of human papillomavirus. International Journal of Cancer. 2005;116:110-115.

[4] Koshiol J, Schroeder J, Jamieson DJ et al. Smoking and Time to Clearance of Human Papillomavirus Infection in HIV-Seropositive and HIV-Seronegative Women. American Journal of Epidemiology. 2006;164:176-183.

[5] National Cancer Institute. Cervical Cancer (PDQ®): Prevention. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/cervical/patient (Accessed August 29, 2006).

[6] Winer RL, Hughes JP, Feng Q et al. Condom Use and the Risk of Genital Human Papillomavirus Infection in Young Women. New England Journal of Medicine. 2006;354:2645-54

[7] Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer, 2006. CA A Cancer Journal for Clinicians. 2006;56:11-25.

[8] Davey E, Barratt A, Irwig L et al. Effect of Study Design and Quality on Unsatisfactory Rates, Cytology Classifications, and Accuracy in Liquid-Based Versus Conventional Cervical Cytology: A Systematic Review. Lancet. 2006;367:122-32.

[9] Solomon D, Davey D, Kurman R et al. The 2001 Bethesda System: Terminology for Reporting Results of Cervical Cytology. JAMA. 2002;287:2114-2119.

[10] Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities. JAMA. 2002;287:2120-2129.

[11] Wright TC, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstetrics and Gynecology. 2004;103:304-308.

[12] Khan MJ, Castle, Lorincz AT et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. Journal of the National Cancer Institute. 2005;97:1072-9.