Screening for Cervical Cancer

Annekathryn Goodman

Almost all cervical cancer is caused by persistent infection with roughly 15 genotypes of human papillomavirus (HPV). The development of new vaccines shown to be efficacious in preventing infection with some of these genotypes offers great promise for the future. It will be a decade or more, however, before primary prevention has an appreciable impact, and screening for cervical cancer will be a primary care priority for the foreseeable future. The best approach to screening for cervical cancer is more uncertain now than it has been for decades. The benefits of cytologic screening with the Papanicolaou (Pap) test are undisputed, but increasing evidence suggests a role for testing for HPV DNA in cervical samples. It is important that the primary care provider stay abreast of new developments in this rapidly changing field.

EPIDEMIOLOGY AND RISK FACTORS (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11)

Epidemiology

In the United States, the current annual incidence of invasive cervical cancer is estimated to be about 13,000 cases, with over 40,000 deaths per year. Fifty percent of cervical cancers in the United States are diagnosed at late stage, usually in older women and Latina women who have not had screening. For an American woman, the lifetime probability of developing invasive cervical cancer is about 0.8%. Worldwide, there are approximately one half million new cases each year and nearly 300,000 deaths.

Risk Factors

Infection with Human Papillomavirus

Cervical cancer is caused by persistent infection with oncogenic genotypes of HPV. Approximately 80% of cervical cancers are associated with the four “high-risk” types of HPV (types 16, 18, 31, and 45); the remaining 20% are associated with 12 other oncogenic types. Specific oncoproteins and inactivated tumor suppressor genes have been identified. Nearly 100% of squamous cell cervical cancer and 75% to 95% of the precursor, cervical intraepithelial neoplasia, have detectable HPV DNA. In considering the epidemiology and risk factors for cervical cancer, it is helpful to think of infection with high-risk HPV as necessary but not sufficient.

Sexual Activity

Behavior that increases the likelihood of transmission of HPV increases the risk for individuals. It is therefore not surprising that first intercourse at a young age (i.e., before age 18 years) and multiple sexual partners (four or more) have been recognized as risk factors for decades.

Additional Risk Factors

Less than 10% of women who become infected with HPV progress to precancerous cervical lesions, and less than 1% develop invasive cervical cancers, suggesting that there must be other factors influencing the persistence of infection, preventing viral clearance, and subsequently leading to cancer. Smoking emerges as an independent risk factor in studies that control for both sexual activity and socioeconomic status. It has been hypothesized that smoking serves as a cofactor, making women more susceptible to the oncogenic effects of viruses.

Similarly, oral contraceptives confer an increase in cervical cancer risk that increases with duration of use and declines after cessation. Parity and the presence of other sexually transmitted diseases are also associated with increased risk. Women infected with HIV are at increased risk of HPV infection; their prevalence of cervical dysplasia ranges from 10% to 60%, depending on the severity of immunosuppression.

NATURAL HISTORY OF CERVICAL CANCER, PRIMARY PREVENTION, AND EFFECTIVENESS OF THERAPY (2, 3, 4 and 5,10, 11, 12, 13, 14, 15, 16 and 17)

Natural History

As noted, though most women are infected with at least one if not more HPV genotypes during their sexual life, 80% of infected women will clear the infection within three years of the exposure. Only about one third of women with HPV infections detected by DNA testing have any evident cytopathology. The peak prevalence of transient HPV infection is during the teenage years or early 20s after the initiation of sexual activity. The peak prevalence of precancerous cervical lesions occurs 10 years later and is followed by the peak prevalence of invasive cancer between 40 and 50 years of age.

Approximately 40% of high-grade squamous intraepithelial lesions (SILs) eventually progress to invasive cancer if left untreated, accounting for approximately 80% of primary cervical cancers. Adenocarcinoma of the cervix accounts for the remaining 20% of invasive cervical cancer and is also associated with HPV infection.

In the absence of primary prevention, when cervical cancer does develop, the mean duration of the detectable asymptomatic period, as estimated historically from incidence and prevalence rates, is very long. For example, the mean duration of carcinoma in situ varies with age but averages about 10 years. The duration of asymptomatic invasive carcinoma is 5 years for all age groups. It should be emphasized that these are estimated means; the proportion of cervical cancers that become invasive early in their development is not known.

In the absence of screening, cervical cancer presents with intermenstrual bleeding, classically prompted by coitus. Symptoms invariably occur late in the course of the disease.

Primary Prevention

Vaccination to prevent HPV infection is a promising primary prevention strategy for cervical cancer. As noted, approximately 80% of cervical cancers are associated with the four “high-risk” types of HPV (types 16, 18, 31, and 45); the remaining 20% are associated with 12 other oncogenic types. HPV-16 is responsible for approximately 50% of cases and is the target of most vaccine development efforts. Vaccines were developed for both prophylactic and therapeutic purposes. Prophylactic use focuses on younger women and girls prior to the onset of sexual activity to prevent
infection. Therapy for those already infected is stimulation of cell-mediated immune responses to latent HPV infection, preventing progression to high-grade intraepithelial lesions.

Vaccine Efficacy

Gardasil (Merck) is a quadrivalent HPV-6/HPV-11/HPV-16/HPV-18 viruslike-particle vaccine shown to have both preventive and therapeutic efficacy. For prevention of precancerous intraepithelial lesions related to HPV-16 and HPV-18, efficacy is estimated at 98% in the population deemed susceptible to infection. Estimated efficacy for lesions caused by HPV-16 and HPV-18 is 44%, and 17% for all high-grade cervical lesions, regardless of etiologic HPV type. Gardasil also protects against HPV-6 and HPV-11 cervical disease and genital warts caused by these genotypes. Cervarix (GSK Biologicals) is a bivalent vaccine that has been shown to be equally efficacious prophylactically. A trial of Cervarix among women with prevalent infection, however, showed no effect on clearance of the virus.

Effectiveness of Treatment

The earlier the clinical stage of the tumor when detected and treated, the better the prognosis. Relative 5-year survival rates for localized and regional invasive carcinoma are about 80% and 40%, respectively. The 5-year experience of one screening program demonstrated that 86% of cases detected by cytologic screening were limited to regional invasion, whereas only 44% of those presenting symptomatically were in this early stage. Survival for carcinoma in situ treated with hysterectomy is essentially 100%. However, the uncertainty about the natural course of carcinoma in situ must be kept in mind.