Rates in the United States have decreased by more than 50 percent, from approximately 14 new cases per 100,000 in 1973 to eight cases per 100,000 women in 1994. Due to this dramatic reduction in the incidence of invasive cervical cancer in industrialized nations, cervical cancer now ranks among the less common female malignancies in the United States. Moreover, recently in some developing countries, age-adjusted cervical cancer mortality rates have decreased due to improved organization of national cervical cancer screening programs and more-efficient utilization of existing resources.
Early detection of cervical cancer is essential, and these reductions are mostly due to the popularization of the Pap smear. Pap smear cervical screening has been accepted by gynecologists as a standard of gynecologic care for years in spite of lack of prospective randomized trials specifically looking at mortality from cervical cancer as an end point. I t is unlikely that further trials evaluating the value of Pap smear screening cytology will be conducted.
Cervical Cancer Risk
Carcinoma of the cervix and its precursors usually occur among women who are sexually active. At the present time, the most important risk factor for cervical cancer appears to be genital infection with high-risk strains of human papillomavirus (HPV), which is usually acquired sexually. Commonly accepted risk factors related to sexual activity and associated with cervical cancer include:
- Early-onset of vaginal intercourse
- A greater number of lifetime sexual partners
- A history of sexually transmitted diseases including HPV infection
Additional factors associated with the risk of cervical dysplasia (abnormal changes in the cells on the surface of the cervix) and cervical cancer include:
- Nutritional status (women with diets low in fruits and vegetables may be at increased risk, and overweight women are more likely to develop adenocarcinoma of the cervix)
- Immune function (HIV, the virus that causes AIDS, damages the body’s immune system and puts women at a higher risk for HPV infections)
Cervical Cancer Screening Tests
Both liquid-based and conventional methods of cervical cytology tests (the study of cells found in the cervix) are acceptable for use in screening. Liquid-based cytology (e.g., ThinPrep®) may have improved sensitivity over conventional Pap smear screening, but at a higher cost. Liquid-based cytology also permits testing of specimens for HPV, which may be useful in guiding management of women whose Pap smears reveal what are known as atypical squamous cells of undetermined significance, or ASCUS. The role and utility of HPV testing as an alternative or in addition to Pap screening continues to evolve. Adding HPV testing to conventional screening may be beneficial.
Most medical societies and organizations agree that screening cytology with the addition of HPV-DNA testing (if both the cervical cytology and the DNA test are negative) should occur every three years. This combined testing is most appropriate for women age 30 and older because HPV is common in younger women and frequently is transient, resolving in one to two years. Women who have undergone a total hysterectomy, with removal of the entire cervix and without a history of cervical dysplasia or cancers, do not require any further Pap tests.
Our Cervical Cancer Screening Guidelines
Our doctors recommend that women have their first cervical cancer screening at age 21, regardless of their age of first sexual intercourse.
For women up to age 30, our doctors recommend cervical cytology testing (which can include Pap smears or liquid-based cytology) every two years.
For women 30 years and older, our doctors recommend one of the following three screening options:
- Cervical cytology testing (which can include Pap smears or liquid-based cytology) every two years.
- Women who have had three negative or satisfactory annual cytology tests may be screened with cytology every three years.
- Cytology plus HPV-DNA test. If both the cytology and the DNA tests are negative, screening should occur every three years.
In addition, women of any age who are immunocompromised due to organ transplant, HIV infection, chemotherapy for cancer, chronic steroid use for chronic renal or bowel disease, or who were exposed in utero to DES (a nonsteroidal synthetic estrogen drug) should be screened annually.
HPV (Human Papillomavirus) Vaccination
Globally more than 5 percent of all cancers are attributed to persistent infection with oncogenic (cancer-associated) HPV. Approximately 274,000 women die annually from cervical cancer, mostly in developing countries where screening by Pap smear is not widely available. The development and broad utilization of the HPV vaccine can have a significant worldwide public health impact.
It is well established that having persistent, high-risk HPV infection in the lower genital tract substantially increases a woman’s risk of developing cervical cancer. High-risk HPV types 16 and 18 are associated with 70 percent of cervical cancers worldwide. Also noteworthy is that these two high-risk types are found in more than 80 percent of cervical adenocarcinomas and adenocarcinoma in situ, which are increasing in rate and are particularly difficult to detect by cytology, histology, or colposcopy. Oncogenic HPV infection is associated with other anogenital cancers in both men and women, including vulvar, vaginal, anal, and penile cancers.
Although not considered cancer causing, HPV types 6 and 11 are associated with 90 percent of anogenital warts, the most common sexually transmitted disease, now affecting 20 to 30 million American men and women. The transmission rate of HPV to the female partners of men with penile warts is high, with more than 70 percent of women developing a genital HPV infection after exposure.
In June 2006, the US Food and Drug Administration approved a prophylactic, quadrivalent HPV vaccine for females aged nine through 26 years. The vaccine is effective against four HPV types — 6, 11, 16, and 18. This human papillomavirus L1 virus-like particle vaccine offers protection against squamous cervical, vulvar, and vaginal cancers as well as dysplasias, adenocarcinoma in situ, and genital warts associated with these HPV genotypes. The vaccine is given in three injections at zero, two, and six months.
The Federal Advisory Committee on I mmunization Practices recommends that the vaccine be routinely given to females aged 11 to 12, but can be given as early as age nine. The vaccine can also be administered as a “catch-up” vaccination for women ages 13 to 26 who did not receive the vaccine earlier. These recommendations have also been endorsed by the American College of Obstetricians and Gynecologists and the American College of Pediatricians. The American Cancer Society (ACS) concurs except in the case of females 19 years and older, since the ACS analysis concludes that there is insufficient evidence to recommend catch-up vaccination of all females over 18. Although studies in older age groups are under way, the concern is that the majority of females over 18 will have already been sexually exposed and possibly already infected, resulting in decreased efficacy of the vaccine.
More than 27,000 women worldwide have been studied with several years of follow-up. These studies have demonstrated continued safety, efficacy, and immunogenicity (eliciting an immune response) against the oncogenic HPV viral types 16 and 18, as well as protection from types 6 and 11. Over an average follow-up time of three years, women who were negative for HPV 16 and 18 and received the vaccine demonstrated 98 percent vaccine efficacy for the primary end point of HPV-16- or 18- related cervical intraepithelial neoplasia grades 2 and 3, adenocarcinoma in situ, and cervical cancer. (A neoplasia is an abnormal formation, or growth of cells, that may lead to the development of a tumor.)
Although most HPV infections clear with time, the regression is dependent on an intact immune system. Immunodeficiency associated with HI V infection, organ or bone marrow transplants, immune-suppressive drugs such as chemotherapy and steroids, as well as the immune senescence of aging make it crucial to identify women who have persistent, oncogenic viral types. The usefulness of the HPV vaccines in these groups has not been established; clearly, regular Pap test screening should continue as well as high-risk HPV testing in combination with the Pap test in women over 30 when appropriate.
The potential to eradicate cervical neoplasias and reduce the incidence of other cancers with continued Pap screening programs and widespread HPV vaccination initiatives is significant. The most effective time to immunize is before the virus is acquired through sexual intercourse (approximate age of first intercourse in US females is between 15 and 16 years of age), prior to peak acquisition of multiple sexual partners (ages 15 to 24), as well as at an age when the vaccine produces the most robust immune response (ages 11 to 13). The safety of the vaccine has been well established. Reports from the first 11 months of US distribution have yielded an overall adverse event rate of 33 in 100,000 doses, with serious adverse events in 1.8 out of 100,000 doses.
Further investigations are needed to determine the efficacy of the vaccine in males, older women, and the immune-deficient patient. Nor is it known how long the immunity will last. Results of ongoing studies in males and older women are anticipated in the next few years. While these issues are under investigation, more than six million Americans are newly infected with HPV each year. The debate about the mandatory use of the HPV vaccine and its prevention of sexually transmitted diseases is difficult for many, but also offers an opportunity for parents and educators to start the discussion about responsible sex. For now, the message is clear: Vaccinate early, and continue to screen with Pap smear regularly.
Recommendations of National and Specialty Organizations for Routine Immunization with Quadrivalent HPV Vaccine
The ACIP recommends routine vaccination of 11- and 12-year-old females with three doses of quadrivalent HPV vaccine; the vaccination series can be started as young as age nine. Vaccination is also recommended for females aged 13 to 26 years who have not been previously vaccinated or who have not completed the full series.
ACOG concurs with the recommendations of the ACIP.
AAP concurs with the recommendation of the ACIP.
SGO “strongly supports and endorses the decision made by the ACIP.”
ACS recommends routine HPV vaccination of 11 and 12 as well as girls as young as age 9. HPV vaccination is also recommended for females aged 13 to 18 years to catch up on missed vaccines or to complete the series. At this time there is not enough evidence for or against vaccination of all 19 to 26 year old females in the general population.
The Gynecology Disease Management Team at Memorial Sloan Kettering supports the recommendations of the ACIP, ACOG, and the SGO for HPV vaccination. We strongly recommend that regular Pap screening be continued for all women, even those who were vaccinated.