Increased performance of Papanicolaou (Pap) smear testing has decreased the incidence and mortality of cervical cancer in the United States over the past four decades. However, this screening test has a 25 to 50 percent false-negative rate. Mandelblatt and associates developed a mathematical model of the natural history of cervical cancer to determine the societal costs and benefits of human papillomavirus (HPV) testing, both alone and combined with Pap smears, and Pap smears alone in the average U.S. population.

The model consisted of 17 hypothetic longitudinal cohorts of 1 million women moving through various states of cervical carcinogenesis during a one-year cycle. Movement between these various states occurred as the women were screened, presented with symptoms, had a hysterectomy (for reasons other than cancer), or died (of any cause). The possible screening strategies were Pap smear with HPV testing, Pap smear alone, and HPV testing alone. The screenings could occur every two or three years beginning at age 20 and continue to age 65, age 75, or death.

An abnormal screening Pap smear was one that showed a low-grade squamous intraepithelial lesion (LSIL) or a more pathologic result, a positive HPV test, or both. A cytologic finding of atypical squamous cells of uncertain significance (ASCUS) was considered a negative result.

The model assumed that cervical cancer reflects the natural history of HPV infection and seldom occurs in the absence of HPV infection, and thus, that untreated HPV infection progresses to high-grade disease and then to invasive cervical cancer. It also assumed that colposcopy would occur only after the HPV test was positive or a diagnosis of LSIL was made, or if ASCUS plus HPV was found. The model assumed that the hypothetic woman received treatment for HPV infection or LSIL and returned to a healthy state and acquired new HPV infection at rates similar to those of women without prior HPV infection or LSIL. A 95 percent cure rate was assumed for women diagnosed with LSIL who underwent cryosurgery, laser surgery, or loop electrosurgical excision procedure (LEEP). Women diagnosed with high-grade squamous intraepithelial lesion (HSIL) who underwent a cone biopsy or simple hysterectomy and had a five-year surveillance were assumed to have a cure rate of 98 percent.

The cumulative lifetime risk of invasive cervical cancer is 3.4 percent in women who do not have screening procedures. All of the considered screening strategies lower this risk. Maximal life years were saved in those who were screened with Pap smears and HPV testing every two years until death. Compared with lifetime biennial Pap testing, 1,367 women would need to be screened to avoid one death; to avoid one case of invasive cancer,472 women would need to be screened every two years with both screening tests. Using HPV screening alone as a strategy would save fewer lives and cost more than the other approaches.

If biennial screening with HPV testing and Pap smears was stopped at age 75, 97.8 percent of the benefit of screening until death would be achieved; this figure drops to 86.6 percent in those screened until 65 years. Combined Pap smears and HPV testing every three years was also cost-effective when compared with use of Pap smears alone for screening every three years.

The authors concluded that Pap smears plus HPV screening every two years will forestall most cases of invasive cervical cancer and death. The risk of this approach is that there will be more false-positive results and, therefore, more colposcopies. There is no clear evidence showing when screening should be stopped; if a women has not received regular screening, she should be tested.