By comparison, 5.18% (95% CI 5.13–5.23%) of all cotests had ASC-US or more severe cytology. Cotesting women aged 30–34 years were the most likely (6.48%) to have an ASC-US or more severe cytology, and cotesting women aged 60–64 years were the least likely (3.17%) to test Hybrid Capture 2 positive. Of note, 2.87% (95% CI 2.84–2.91%) of cotests in women aged 30 years and older had ASC-US or more severe cytology and tested Hybrid Capture 2 negative. Women aged 45–49 years were the most likely (3.77%) to have ASC-US or more severe cytology and test Hybrid Capture 2 negative.
In our experience of 800,000 cotests, we found that the likelihood of testing Hybrid Capture 2 positive was much less than was previously reported in smaller epidemiologic studies or selected populations in the United States.15,16 The percentage of carcinogenic HPV test positives, as measured using Hybrid Capture 2, was 6.27%. Not surprisingly, the highest percentage of Hybrid Capture 2 positives was found in women aged 30–34 years (10.82%) and women aged 35–39 years (8.03%), in the age group of Kaiser Permanente Northern California female membership with highest prevalence of CIN 2/3 (data not shown). These data are consistent with the prevalence of HPV in women of those ages participating in the HPV Sentinel Surveillance project,15 in which more than half of the women enrolled in that study were between the ages of 30 and 39 years and thus partially explaining the observed high HPV prevalence. There was the expected and pronounced decrease in HPV prevalence in the older Kaiser Permanente Northern California female membership. Thus, the concerns raised about introduction of HPV testing into clinical practice19 may be seen to have been overstated when population screening data are considered.
Although these are data from a large population, we point out that these data may not be generalizable to all populations worldwide. The likelihood of testing HPV positive in conjunction with cotesting is population specific and depends on the age and risk behaviors in that population.
The percentage of Hybrid Capture 2 positive results among cytologically normal women observed at Kaiser (3.99%) was similar to the percentage (3.7%) of carcinogenic HPV positives in cytologically normal women reported in a population-based study of 44,102 women using a GP5+/6+ polymerase chain reaction assay, which has shown to have comparable clinical performance to Hybrid Capture 2.20 The percentage is also similar to the median percentage of HPV positives (4%) in all women aged 30 years and older as reported in a survey conducted by the College of American Pathologists.21 Interestingly, we found that the likelihood of testing carcinogenic HPV positive but cytologic negative to be only slightly more common than the likelihood of testing carcinogenic HPV negative but cytologic positive (3.99% compared with 2.90%), which is primarily (HPV-negative) ASC-US cytology (82.8%) that bears a very low risk of CIN 2/322 but also requires increased surveillance and clinical follow-up according to current guidelines.11
Although Kaiser uses conventional Pap tests for detection of cytologic abnormalities while approximately 90% of U.S. clinics rely on liquid-based cytology, a recent meta-analysis23 indicates that liquid-based cervical cytology is not more sensitive and may be less specific for detection of high-grade cervical intraepithelial neoplasia than the Pap test. Thus, the use of liquid-based cervical cytology, widely adopted in advance without evidence of greater screening accuracy compared with conventional Pap tests,24 would be expected to increase the proportion of test positives by cytology, including false positives. Regardless, the use of Pap test (compared with liquid-based cytology) at Kaiser does not alter our observations about HPV testing.
Recognition of cytologically normal, HPV-negative women is important because extension of screening intervals from 1 to 3 years based on negative cytology alone, despite being preceded by three consecutive negative cytology results, triples the risk of invasive cervical cancer.25 Although unfamiliar with the research, many women and providers intuitively understand that fewer Pap tests mean more cancer risk, and the majority of women and medical care providers participating in screening in our population and that of the Southern California Kaiser Permanente Medical Care Plan were unwilling to accept recommendations made by the Kaiser clinicians in the 1980s and 1990s to abandon annual screening with cytology alone in favor of longer screening intervals (data not shown).
As the morbidities associated with the treatment of dysplasia have become more apparent,26–28 and it has been recognized that half of CIN 2 (which is routinely treated) regresses in 24 months,29,30 the adverse consequences for the patient of annual screening come into sharper focus. Currently Kaiser Permanente Northern California offers screening with Pap and HPV at 3-year intervals or screening with cytology at more frequent intervals to our female members aged 30 years and older. During the period from December 1, 2006, through February 26, 2007, 91.6% of Kaiser Permanente Northern California members aged 30 years and older who participated in screening elected the cotesting option (screening every 3 years if Pap and HPV were both negative) instead of annual screening. Providing the reassurance required to move away from annual screening is one of the benefits of cotesting that we have observed.
We will be conducting subsequent analyses on the predictive values for CIN 2 or more severe, CIN 3 or more severe, and cancer of all pair-wise cotesting results. However, we already recognize that women who test positive for carcinogenic HPV and negative by cytology are at an elevated risk for cervical precancer and cancer compared with women who test negative on both,13,31 and yet the positive predictive value of a single Pap-negative, HPV-positive cotest for CIN 3 or more severe remains less than ideal. Thus, the development of a viable strategy for identifying the subset of Pap-negative; HPV-positive women at highest risk of CIN 3 or more severe would further improve the efficiency of secondary cervical cancer prevention. Future clinical research will need to focus on identifying the best strategies for managing women who test positive for carcinogenic HPV and negative by cytology, which may include HPV genotyping for HPV16, HPV18, and possibly HPV4511,32,33 or immunodetection of p16INK4a.34
1.Kitchener HC, Castle PE, Cox JT. Chapter 7: Achievements and limitations of cervical cytology screening. Vaccine 2006;24:S63–70.
2.Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119:1095–101.
3.Cuzick J. Role of HPV testing in clinical practice. Virus Res 2002;89:263–9.
4.Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology. The 1992 National Cancer Institute Workshop. JAMA 1994;271:1866–9.
5.Castle PE, Wheeler CM, Solomon D, Schiffman M, Peyton CL. Interlaboratory reliability of Hybrid Capture 2. Am J Clin Pathol 2004;122:238–45.
6.Carozzi FM, Del Mistro A, Confortini M, Sani C, Puliti D, Trevisan R, et al. Reproducibility of HPV DNA testing by Hybrid Capture 2 in a screening setting. Am J Clin Pathol 2005;124:716–21.
7.Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 2006;24:S78–89.
8.Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007;357:1579–88.
9.Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357:1589–97.
10.Bulkmans N, Berkhof J, Rozendaal L, van Kemenade F, Boeke A, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764–72.
11.Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346–55.
12.Wright TC Jr, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304–9.
13.Sherman ME, Lorincz AT, Scott DR, Wacholder S, Castle PE, Glass AG, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst 2003;95:46–52.
14.Kjaer S, Hogdall E, Frederiksen K, Munk C, van den Brule A, Svare E, et al. The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res 2006;66:10630–6.
15.Datta SD, Koutsky LA, Ratelle S, Unger ER, Shlay J, McClain T, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003–2005. Ann Intern Med 2008;148:493–500.
16.Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA 2007;297:813–9.
17.Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120–9.
18.Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342–62.
19.Sawaya GF. Adding human papillomavirus testing to cytology for primary cervical cancer screening: shooting first and asking questions later. Ann Intern Med 2008;148:557–9.
20.Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764–72.
21.Moriarty AT, Schwartz MR, Eversole G, Means M, Clayton A, Souers R, et al. Human papillomavirus testing and reporting rates: practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytology in 2006. Arch Pathol Lab Med 2008;132:1290–4.
22.Safaeian M, Solomon D, Wacholder S, Schiffman M, Castle P. Risk of precancer and follow-up management strategies for women with human papillomavirus-negative atypical squamous cells of undetermined significance. Obstet Gynecol 2007;109:1325–31.
23.Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol 2008;111:167–77.
24.Sawaya GF. Evidence-based medicine versus liquid-based cytology. Obstet Gynecol 2008;111:2–3.
25.Sawaya GF, McConnell KJ, Kulasingam SL, Lawson HW, Kerlikowske K, Melnikow J, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med 2003;349:1501–9.
26.Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489–98.
27.Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284.
28.Albrechtsen S, Rasmussen S, Thoresen S, Irgens LM, Iversen OE. Pregnancy outcome in women before and after cervical conisation: population based cohort study. BMJ 2008;337:a1343.
29.ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 2003;188:1393–400.
30.ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:1383–92.
31.Castle PE, Sideri M, Jeronimo J, Solomon D, Schiffman M. Risk assessment to guide the prevention of cervical cancer. Am J Obstet Gynecol 2007;197:356.e1–6.
32.Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, 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. J Natl Cancer Inst 2005;97:1072–9.
33.Castle PE. Invited commentary: is monitoring of human papillomavirus infection for viral persistence ready for use in cervical cancer screening? Am J Epidemiol 2008;168:138–44.
34.Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, Gillio-Tos A, De Marco L, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008; 9:937–45.
Figure. No caption available.