For women in the United States, a Papanicolaou (Pap) test has become a standard part of their annual gynecologic exam. Also known as a Pap smear, the test, which was first made public in 1943 when George Papanicolaou and Herbert Traut published their landmark paper Diagnosis of Uterine Cancer by the Vaginal Smear, revolutionized the field of cervical cancer prevention by allowing physicians to detect and treat cervical cancer in its earliest stages. In countries with the resources for screening and treatment, widespread cervical cancer screening programs continue to lead to dramatic declines in deaths from this disease.
In spite of this progress, nearly 10,000 women each year are diagnosed with cervical cancer in the United States, and the number of women who undergo treatment for precancerous changes to the cervix is many times larger than that. Worldwide, an estimated 231,000 women die of cervical cancer each year, with 80 percent of those deaths occurring among women in developing countries.
But things may soon be changing. For many years it’s been known that virtually all cases of cervical cancer are linked with a common viral infection known as human papillomavirus (HPV). Once the link with an infectious agent was confirmed, important avenues of research opened up. These included the development of tests to identify women infected with high-risk types of HPV and the development of vaccines to prevent the infection. Use of these vaccines may have the greatest impact on cervical cancer incidence and mortality since the advent of the Pap test.
What Is Cervical Cancer?
The cervix forms the opening to the uterus from the vagina. It is covered with two main types of cells: squamous cells, which cover the part of the cervix that extends into the vagina, and columnar cells, which line the cervical opening. Most cervical cancers develop close to where these two cell types come together, in an area called the transformation zone. Once cervical cancer develops, it can spread throughout the cervix to neighboring organs or to distant sites in the body.
Cancerous and precancerous changes in cervical cells are often first detected by a Pap test, wherein a sample of cells is removed from the cervix using a small wooden or plastic spatula and a brush. The cells are then examined under a microscope in a laboratory. If Pap test results are abnormal, a physician may perform a colposcopy, using 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 the 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.
The Link with HPV
Human papillomaviruses consist of more than 100 different viruses. 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.
According to Dr. Laura Koutsky, professor of epidemiology at the University of Washington School of Public Health and Community Medicine, the study of infectious causes of cervical cancer has a long history. “There are data back to the eighteenth century, showing that married women are more likely to die of cervical cancer than nuns.” This observation suggested a link between cervical cancer and a sexually transmitted infection, but the link with HPV would be long in coming. According to Dr. Koutsky, part of the challenge of studying HPV was that it could not be grown in cell or tissue cultures like some other organisms. It would take the molecular techniques that were introduced in the 1970s to adequately study and understand the virus. Once these techniques were applied, it became apparent that most cervical cancers contained evidence of HPV.
Infection with a high-risk type of HPV does not necessarily lead to cancer. Many infections disappear on their own, and others may persist without causing cancer. Infection does, however, increase the risk of cancer, and virtually all cases of cervical cancer can be linked to infection with a high-risk type of HPV.
The recognition that specific types of HPV are the cause of cervical cancer led to the development of tests to identify women infected with high-risk types of HPV. Hybrid Capture® 2, for example, tests for the presence of 13 high-risk types of HPV. Information about HPV status may guide decisions about follow-up care.
One important use for HPV testing is further evaluation of women with an indeterminate Pap test result (atypical squamous cells of uncertain significance, or ASCUS). Women with ASCUS 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.
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. The combination of HPV testing and Pap testing may not be recommended for screening younger women because many will have HPV infections that will clear without causing precancerous cervical lesions.
HPV vaccines fall into two broad categories: preventive and therapeutic. Preventive vaccines are designed to prevent infection with the virus, whereas therapeutic vaccines would treat the infection, precancerous lesion, or cancer in individuals who are already infected. Although prevention of infection is the ultimate goal, treatment of existing infections and cervical changes would benefit the many women who are currently infected.
The two vaccines that are farthest along in development are preventive vaccines. Gardasil™ (quadrivalent human papillomavirus [types 6, 11, 16, 18] recombinant vaccine), developed by Merck, targets HPV types 6 and 11 (which are linked with genital warts) as well as the cancer-associated types 16 and 18. Cervarix™ (bivalent HPV 16/18 L1 viruslike particle AS04 vaccine), developed by GlaxoSmithKline, targets HPV types 16 and 18 only. Clinical trials of these vaccines suggest that they are likely safe and highly effective. The duration of effectiveness is still uncertain, but it appears to be at least four to five years. Because HPV types 16 and 18 are thought to account for roughly 70 percent of all cases of cervical cancer, widespread use of these vaccines would have the potential to eliminate most (but not all) cases of cervical cancer and precancerous changes to the cervix.
Dr. Koutsky emphasizes that both Gardasil and Cervarix 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, the vaccines are likely to have the greatest effect when administered before the teen years. In addition to being less likely than older children to be sexually active, younger children versus older adolescent and young adult women appear to develop a stronger immune response after HPV vaccination. This may increase vaccine effectiveness.
Dr. Koutsky also notes that to have the greatest impact it will ultimately be important to vaccinate both girls and boys. Vaccinating a larger number of individuals will reduce transmission of these viruses in the community and will make it less likely that an unvaccinated individual will become infected. Furthermore, in addition to reducing the risk of cervical cancer, the vaccines are likely to reduce the risk of other HPV-related cancers, such as cancer of the penis, anus, and oropharynx (part of the throat). Protection against genital warts would also benefit both boys and girls.
In June 2006, Gardasil was approved by the U.S. Food and Drug Administration (FDA) for use in girls and women between the ages of nine and 26 years. Approval for use in males may be considered after more data become available. GlaxoSmithKline has applied to the FDA for approval of Cervarix.
The issue of vaccinating preteens for a sexually transmitted infection has prompted discussion of whether parents will accept the vaccine for their children and whether physicians will recommend it. Researchers working in this area, however, suggest that proper education of parents and physicians may alleviate concerns. One study, for example, found that providing an information sheet about HPV prompted many parents to accept the vaccine for their children: 37 percent of parents who were initially opposed decided to accept vaccination, and 65 percent of parents who were initially undecided chose to accept vaccination.
Pap Test Still Important
Even with the introduction of a vaccine to prevent HPV, the Pap test will continue to play an important role in women’s health. The currently licensed vaccine does not prevent infection with all high-risk types of HPV and therefore will not eliminate all cases of cervical cancer; nor does this vaccine treat HPV infections in women who are already infected. Among uninfected women who receive the vaccine, however, the frequency of precancerous changes to the cervix is likely to be greatly reduced. This will reduce anxiety and the need for follow-up procedures.
Now approved by the FDA, Gardasil has the potential to dramatically reduce the burden of precancerous and cancerous changes to the cervix by preventing infection with high-risk types of HPV. If Cervarix is approved, it too will be one more weapon in the arsenal against cervical cancer. And for women with existing HPV infections, research into therapeutic vaccines continues.
The work of Dr. George Papanicolaou allowed doctors to detect and treat very early cervical abnormalities. The development of HPV vaccines takes this work one step further by eliminating the cause of these abnormalities. Though the need for cervical cancer screening has not been eliminated, the outcome of screening is likely to change for the better for many women.
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