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ORIGINAL RESEARCH |
From the Departments of Public Health, Obstetrics, and Gynecology, and Family Medicine, Denver Health and Hospital Authority; and Departments of Preventive Medicine and Biometrics, Family Medicine, Medicine, and Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, Colorado.
Address reprint requests to: Judith C. Shlay, MD Denver Public Health 605 Bannock St. Denver, CO 80204-4507 E-mail: jshlay{at}dhha.org
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Abstract |
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Methods: One hundred ninety-five consenting women were referred for colposcopy because of atypia on Papanicolaou smears between September 1997 and April 1999. Before colposcopy, women completed risk assessments and had cervical swabs collected for HPV testing using the Hybrid Capture-II assay (Digene Corporation, Silver Spring, MD). Associations of demographic and clinical variables were assessed by 
2 analysis, and logistic regression was used to assess factors associated with CIN 2–3. The cost-effectiveness of routine colposcopy versus reflex HPV testing by either conventional or liquid-based Papanicolaou smear media was compared.
Results: Cervical intraepithelial neoplasia was diagnosed in 70 of 195 women (35.9%), 55 (28.2%) with CIN 1 and 15 (7.7%) with CIN 2–3. High-risk HPV types were detected in 31.3% of all subjects, 36.4% of those with CIN 1, and 93.3% of those with CIN 2–3. By logistic regression, CIN 2–3 was associated only with detection of high-risk HPV (odds ratio 110.08, 95% confidence interval 8.35, 999.00). The sensitivity of high-risk HPV for detecting CIN 2–3 was 93.3%, specificity 73.9%, positive predictive value 23.0%, and negative predictive value 99.3%. The cost of reflex HPV testing using conventional smear or liquid-based media was less than routine colposcopy ($4809 and $4308, respectively, versus $4875 per case detected).
Conclusions: Triage based on HPV testing would result in referral of approximately 31% of patients to colposcopy and appears to be a sensitive and cost-effective alternative to colposcopy.
The National Cancer Institute estimates that 50 million Papanicolaou smears are done annually in the United States, approximately 2.5 million of which show evidence of low-grade abnormalities.1 In cervical cancer prevention programs, the optimal treatment of low-grade abnormalities is controversial, with recommendations ranging from repeat Papanicolaou smears at short intervals, to universal colposcopy and biopsy.2–4 It has been reported that 5–10% of women with atypia will have CIN 2–3 on biopsy.2,5–7
Previous studies that evaluated risk factors for CIN suggested links with sexually transmitted diseases (STDs), high parity, oral contraceptive use, cigarette smoking, and multiple partners,8,9 and recent reports indicated the possible value of risk assessment for predicting CIN 2–3 among women with low-grade abnormalities.10–12 Such an approach, if confirmed in other settings, could be clinically useful for targeting women who should have high priority for colposcopy.
Human papillomavirus (HPV) infection is a well-established etiologic agent in cervical neoplasia,13,14 and specific HPV types consistently have been associated with high-grade CIN and invasive cervical cancer.13,14 There has been interest in using HPV testing in triage of women with low-grade cytologic abnormalities.5–7,15–20 Initial studies yielded conflicting results,5–7,16–18 partly because of differing patient characteristics and HPV test sensitivities,5–7,18 although recent studies using more sensitive tests reported more promising performance.15,19,20
At our institution, an urban public hospital system that serves a predominantly indigent and minority population, all women with a single atypical smear are referred for colposcopy, a common approach when compliance with follow-up is believed to be uncertain.1 However, that strategy results in a large colposcopy burden and potential psychologic distress for the women having them.21 The purpose of this study was to determine the usefulness of patient demographic and clinical characteristics and HPV testing for predicting CIN 2–3 on biopsies in women who had atypia on Papanicolaou smears.
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Materials and Methods |
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Study visits were a median of 64 days (range 12–430 days) after atypical Papanicolaou smear results. At those visits, women completed questionnaires that included demographic and clinical information, then had colposcopic examinations. Specimens for HPV testing were collected with a cervical brush (Digene Corporation, Silver Spring, MD), which was placed in specimen transport medium (Digene Corporation) and frozen at -20C. After application of 5% acetic acid to the cervix, colposcopy was done. A biopsy was done for colposcopically abnormal appearing areas, and all women, including those with normal colposcopic examinations, had endocervical brushing of the endocervical canal.
Cervical biopsies and endocervical brushings were read using the conventional CIN-based system22 through the Anatomic Pathology Department at Denver Health. Laboratory personnel were unaware whether patients participated in the study and were blinded to behavioral risk factors and HPV test results. Samples were assayed by the Hybrid Capture II microplate method (Digene Corporation, Silver Springs, MD), according to manufacturer’s instructions, in the Virology Laboratory of Denver Public Health. Two probe mixes were used to detect any of five low-risk HPV types (6, 11, 42, 43, 44) and any of 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). Triplicate assay controls were done for high- and low-risk probes. Specimens were considered positive for high- or low-risk HPV types if assays’ chemiluminescence was at or above 1.0 pg/mL. Individuals with either high-risk HPV or high- and low-risk HPV were designated as having high-risk HPV. Laboratory personnel were blinded to results of questionnaires and biopsy results. For sample size calculations, we assumed that 6% of women would have CIN 2–3 and 30% of women without CIN 2–3 would have high-risk HPV.5 Thus, with 195 women, the study had 80% power to detect a minimum odds ratio (OR) of 5.2 at the .05 level of significance for the association between high-risk HPV and CIN 2–3.
Associations between demographic and clinical variables and high-risk HPV infection and CIN 2–3 were assessed by 2 analysis. The Mantel-Haenszel trend test was used to test for a linear association between continuous variables and outcomes.23 Sequential logistic regression modeling was done23 with variables that were significant by univariate analysis at P 
.20 or that were considered clinically relevant. Sensitivity, specificity, positive predictive, and negative predictive values of detection of high-risk types of HPV for CIN 2–3 were calculated. We used SAS version 6.12 software (SAS Institute Inc., Cary, NC) for all analyses.
A limited cost-effectiveness analysis of strategies used to treat atypia in our population was done to compare routine colposcopy with triage by reflex HPV testing,20 using either conventional Papanicolaou smear with a vial of specimen transport medium collected for possible HPV testing or Papanicolaou smear using liquid-based media with HPV testing on the residual sample. According to data from a previous study,19 the HPV testing strategy assumed that women who tested negative for high-risk HPV would have follow-up Papanicolaou smears 6 months later (Figure 1
). The cost of an HPV test using only the high-risk probe was estimated at $48.50 (current Health Care Finance Administration 1999 Fee Schedule HPV testing current procedural terminology code). For HPV testing in conjunction with conventional Papanicolaou smears, the cost of the specimen transport medium was estimated at $1.00 (Digene Corporation, personal communication) and our laboratory cost for storage of specimen transport medium, before a decision whether to conduct HPV testing was estimated at $6.50 (Denver Health Laboratory, personal communication). For the liquid-based Papanicolaou smear media, the incremental cost over conventional Papanicolaou smear testing was estimated to be $5.60.24 The same source was used to estimate the costs of office visits with Papanicolaou smears ($38.68) and colposcopies with cervical biopsies and endocervical brushings ($375).24 The analysis assumed a 30% loss to follow-up for repeat Papanicolaou testing.25
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Results |
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. The median age was 33 years (range 15–76 years), and race-ethnicity distribution was 21% white, 16% black, 57% Hispanic, and 6% other ethnicities. Most (85%) participants were either on Medicaid or were uninsured. All were sexually active, with a median age at first intercourse of 17 years (range 8–29 years) and a median number of lifetime sex partners of three (range 1–100 partners). Half the women had histories of abnormal Papanicolaou smears and 37% had histories of STDs. Overall, 73 (37.4%) women were HPV-positive, 46 (23.6%) with a high-risk type, 15 (7.7%) with high-risk and low-risk types, and 12 (6.2%) with only a low-risk type. High-risk HPV infection was significantly more common in women under 30 years old (48.7%) than in those 30 years or older (28.6%) (P < .001).
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Detection of a high-risk type of HPV infection was associated with a 32.7 times increase (23.0% versus 0.7%) in histologic confirmation of CIN 2–3 lesion (P < .001). By univariate analysis, no factor except detection of high-risk HPV infection was associated with CIN 2–3. By sequential logistic regression modeling, CIN 2–3 was associated only with high-risk HPV (OR 110.08, 95% CI 8.35, 999.00) (Table 2). Negative confounding occurred when all other variables were included in the model, especially age and race, causing an increase in the OR of HPV.
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shows the overall performance characteristics of HPV testing by Hybrid Capture II for prediction of CIN 2–3 and is stratified by age. Triage based on HPV testing would result in 31% of women with atypia being referred for colposcopy. Among women under 30 years old, sensitivity was 100% and specificity 57.4%; whereas among women at least 30 years old, sensitivity was 85.7% and specificity 83.9%. There was no difference in performance of HPV testing for detecting CIN 2–3 in women with and without histories of previous abnormal smears or histories of treatment for abnormal smears.
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. Based on the costs estimated in the Methods section, colposcopies for all women would detect all cases of CIN 2–3 at a cost of $4875.00 per case detected (Table 4). The HPV triage strategy using conventional Papanicolaou smears was conservatively assumed to detect only 93% of CIN 2–3 cases, at a cost of $4809.28 per case detected. If follow-up visits increased sensitivity by 7.7%, as estimated by Manos et al,19 then sensitivity of that approach would be 100% and cost per case of CIN 2–3 detected would be $4488.66. The HPV triage strategy using liquid-based Papanicolaou smear media would be least expensive, at $4307.95 per case detected if sensitivity was 93% and $4020.75 per case detected if sensitivity was 100%.
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Discussion |
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The inverse relationship of HPV infection with age among the women with atypia might have implications for the use of HPV testing for triage of women with atypia. We found age-related differences in the performance of HPV testing for detecting CIN 2–3, with greater specificity in older women and greater sensitivity in younger women. That association was not noted in studies of earlier-generation HPV tests7,18 but has been found in several reports that analyzed the Hybrid Capture II assay,15,20 including the study by Manos et al,19 which had sensitivity estimates of 100% in women under 30 years old and 81% in women over 30,26 similar to our study. It was suggested that HPV lesions of more recent onset might exfoliate more virus, whereas lesions associated with persistent infection and a partial immune response might be more localized and have a lower and less easily detectable mucosal viral load.27 Among women with CIN, a higher prevalence of HPV DNA by the Hybrid Capture I assay and polymerase chain reaction was reported in women under 35 years old than in older women.28 The age-related difference in performance of HPV testing might have age-specific clinical implications. For example, because younger women have a higher prevalence of HPV infections, a greater potential for CIN lesions to resolve spontaneously,29 and a longer period before peak occurrence of cervical cancer,30 problems with specificity will be more important than inadequate sensitivity. In contrast, given the same considerations, suboptimal sensitivity will be more important among older women. Those issues support the notion that age-specific thresholds for defining positive HPV test results might be useful for optimizing the influence of HPV testing for triage of low-grade abnormalities.26,31 Pending such changes and with the current format of the Hybrid Capture II test, the need for repeat Papanicolaou smears in 6 months for HPV-negative women19 (Figure 1
) appears to be low in younger women, when the test has excellent sensitivity. Further studies are needed to clarify the effect of age, prior treatment, and other factors on test performance.
Our cost-effectiveness analysis indicated that strategies using reflex HPV testing for triage might be more cost-effective than strategies that refer all women for colposcopy. Reflex HPV testing can be done in programs that use conventional slide-based cytology. However, expenses associated with collecting additional samples for possible HPV testing on all women who are screened appear to make this less cost-effective than converting to liquid-based Papanicolaou screening, although local variations in cost will likely influence the relative cost-effectiveness of those two strategies. This result differs from those of previous studies that assessed cost-effectiveness of HPV testing7,18,32 using earlier and less sensitive generations of HPV tests. Compared with our current approach of referring all women with atypia for colposcopy, using HPV testing for triage would decrease the number of colposcopic examinations by approximately 65%, while maintaining sensitivity over 90%. Although sensitivity of the HPV testing strategy was not 100%, its real-world clinical performance could be more sensitive than referring all women for colposcopies. The subset of women referred for colposcopy because of HPV-positive atypia might be more motivated to follow through with their evaluations because there is less uncertainty about the meaning of their atypical smears. Women with HPV-negative atypia might be less anxious when informed of the low-grade abnormality. More detailed cost-effective analyses assessing sensitivity of outcomes to varying levels of test performance and costs, and the psychologic costs of various treatment strategies, are needed.
Our investigation had several potential limitations. Information was not available on the number of women who refused participation in the study, so we could not compare characteristics of enrolled participants to non-participants. Our HPV tests were not part of a reflex testing strategy, but were done at colposcopy approximately 9 weeks later, during which time infection detectable at the initial smear could have cleared or new infection been acquired, leading to imprecise classification of HPV status. Initial smears and cervical biopsy specimens were not reviewed by a single pathologist, but all pathology and cytology readings were masked to HPV test results. We did not do Papanicolaou smear testing at colposcopy, thus we were unable to assess the performance of repeat Papanicolaou smear testing. Our small sample made associations between demographic and clinical characteristics and CIN 2–3 possibly not detected. The cost-effectiveness analysis did not consider certain costs associated with being referred to colposcopy (eg, missed appointments and the need to reappoint those patients) or the counseling requirements of informing a woman that she has a cancer-associated sexually transmitted viral infection that is incurable.33
Despite those limitations, our findings support the potential use of HPV testing for predicting CIN 2–3 in women with atypia in several populations. Current large-scale randomized clinical trials of HPV testing for triage of women with low-grade Papanicolaou smear abnormalities should provide more complete information on the effect of this strategy on clinical outcome and cost-effectiveness.17
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Footnotes |
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We are grateful to Xinyue Hou for performing human papillomavirus assays, to Marybeth Haas, Jake Kaminisky, Joyce Kanwai, and Dana Nzirubusa for enrolling patients at the Women’s Care Clinic; to Mary Virginia Hildred for retrieving human papillomavirus samples; and to Mohammed Malakouti for the development of the computer database.
Received December 10, 1999. Received in revised form March 6, 2000. Accepted April 7, 2000.
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2. Kinney W, Manos M, Hurley L, Ransley J. Where’s the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses. Obstet Gynecol 1998;91:973–6.[Abstract]
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6. Ferris D, Wright T, Litaker M, Richart R, Lorincz A, Sun X, et al. Triage of women with ASCUS and LSIL on Papanicolaou smear reports: Management by repeat Pap smear, HPV DNA testing, or colposcopy. J Fam Pract 1998;46:125–34.[Medline]
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