Affiliations of authors: European Network for Cervical Cancer Screening and Unit for Evaluation of Cancer Screening Programmes, Scientific Institute of Public Health, Brussels, Belgium (MA); Centre for Evidence Based Medicine, Belgian Branch of the Cochrane Collaboration, Department of General Practice, University of Leuven, Leuven, Belgium, and University of Maastricht, Maastricht, The Netherlands (FB); Department of Clinical and Epidemiological Virology, University of Leuven (MVR); Department of Obstetrics and Gynaecology, University Hospital of Ioannina, Ioannina, Greece (EP); Central Lancashire Teaching Hospitals, Preston, UK (PMH); Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden (JD).
Correspondence to: Marc Arbyn, MD, MSc, Scientific Institute of Public Health, J. Wytsmanstreet 14, B1050 Brussels, Belgium (e-mail: marc.arbyn{at}iph.fgov.be)
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ABSTRACT |
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INTRODUCTION |
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The natural history of minor cytologic lesions is difficult to predict on the basis of cytomorphologic grounds. These lesions often regress spontaneously and do not require treatment (1416). Referring all women with minor cytologic lesions for further gynecologic exploration would, therefore, mean an increase in overdiagnosis and overtreatment (12,17). Lack of availability of colposcopic services at affordable prices often makes such an approach unrealistic. Nevertheless, although most women with an ASCUS smear result do not have clinically significant disease, a substantial proportion of them do have histopathologically confirmed high-grade cervical intraepithelial neoplasia or worse (CIN2+) (1820). Indeed, from a population of screened U.S. women, it was estimated that one-third of CIN2+ lesions were discovered on follow-up of a previous smear with ASCUS (20).
Given the evidence concerning the etiologic role of oncogenic human papillomavirus (HPV) infections in the development of cervical cancer and CIN (2125), HPV testing has been proposed as a triage method to identify women at increased risk of cervical cancer and thus requiring referral for colposcopic exploration (18,19). However, results concerning the utility of HPV triage for women with equivocal cytology are inconsistent (2628). We therefore used meta-analytic tools to extract from the literature all available data concerning diagnostic accuracy parameters, studied the variation in a systematic way, and obtained overall synthetic measures.
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METHODS |
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In this meta-analysis, we addressed the following questions: 1) What is the accuracy (i.e., sensitivity, specificity, predictive values, and likelihood ratios) of HPV DNA testing to detect histologically confirmed CIN2+ disease in women with an index smear showing ASCUS? 2) In studies in which the Pap smear was repeated, what is the accuracy of repeat cytology at thresholds of ASCUS, LSIL, and HSIL (high-grade squamous intraepithelial lesion) to detect CIN2+? and 3) What are the differences in accuracy between both triage tests?
Retrieval Strategy
A systematic literature search identified articles published between 1992 and 2002 that contained quantitative data allowing assessment of one or more of the research questions. Articles were retrieved from the electronic bibliographic databases (MEDLINE, EMBASE, Cochrane Library) using the following search terms: (((cervix OR cervical) AND (cancer OR carcinoma OR neoplas* OR dysplas* OR CIN OR SIL)) OR (cervix neoplasm)) AND (HPV OR human papillomavirus) AND (triage OR management). The search was completed manually by searching the reference lists of relevant articles and by screening the tables of contents (for 19922002) of the following journals: American Journal of Obstetrics and Gynecology, European Journal of Gynecological Oncology, Journal of Gynecological Oncology, Journal of Lower Genital Tract Disease, Journal of Reproductive Medicine, and Obstetrics and Gynecology. References were selected if they fulfilled three inclusion criteria: 1) women in the study presented with an index Pap smear of the uterine cervix with atypical squamous/glandular cells of unspecified significance (ASCUS/AGUS); 2) an HPV DNA detection test was performed; and 3) women were subsequently subjected to colposcopy and colposcopy-directed biopsies, with or without endocervical curettage, for histologic verification. A fourth but non-obligatory criterion was the repetition of the Pap test.
For several studies, we considered limited information. From Ferris et al. (29,30), we selected the HPV DNA data from the Hybrid Capture I assay because these data were contrasted with repeat cytology; from Morin et al. (31), HPV data from the Hybrid Capture II assay were used; and from the ASCUS-LSIL Triage Study (ALTS) (32,33), we used results from two of the three experimental arms: women randomly assigned to immediate colposcopic verification and women randomly assigned to the HPV DNA testing arm, in which colposcopy was restricted to women showing presence of high-risk HPV DNA or HSIL on the repeat smear (32).
Thresholds for Triage Tests
We considered a single threshold for HPV positivity: the presence of HPV DNA at a level greater than the cutoff for a positive test as stated by the test manufacturer. The variation in accuracy according to other thresholds of increasing viral load was studied by a summary receiver operating characteristic curve analysis and is reported elsewhere (34). We retrieved information on the presence of oncogenic and high-risk HPV types only. We considered three threshold levels for abnormal cytology on the repeat Pap test: ASCUS or worse, LSIL or worse, and HSIL or worse. The 1991 version of the Bethesda Reporting System (35) was used for cytologic classification.
Outcome
The histologic result was used as the gold standard. We assumed that histologic examination of material obtained by colposcopy-directed biopsy, loop excision, or endocervical curettage provided complete ascertainment of the considered disease status. Throughout our systematic review, we used the CIN nomenclature to describe histologic outcomes (36). We considered only the outcome of CIN2+.
Covariate Information
The following study properties were summarized in comprehensive tables: characteristics of the study population (place, inclusion and exclusion criteria, study size, and age distribution), properties of the HPV DNA testing systems (type of DNA detection method, collection device, transport medium), repeat cytology (conventional or liquid-based preparation, cytologic threshold, collection device), procedures for gold standard verification, and the blinding of interpreters for other test results.
Definition of Accuracy Measures and Statistical Analysis
The numbers of true-positives, false-negatives, false-positives, and true-negatives defined at the considered thresholds were extracted from each study, and the following accuracy parameters were calculated: sensitivity (true-positives/[true-positives plus false-negatives]); specificity (true-negatives/ [true-negatives plus false-positives]); positive predictive value (true-positives/[true-positives plus false-positives]); negative predictive value (true-negatives/[true-negatives plus false-negatives]); test-positivity rate ([true-positives plus false-positives]/total number of patients), and prevalence of disease defined as presence of CIN2+ ([true-positives plus false-negatives]/total number of patients). The positive likelihood ratio (PLR = sensitivity/[1 specificity]) and the negative likelihood ratio (NLR = [1 sensitivity]/specificity) express the likelihood of the presence of CIN2+ versus the absence of CIN2+ when tests are positive or negative, respectively. The positive likelihood ratio should be greater than unity and as large as possible, whereas the negative likelihood ratio should be less than unity and tend toward zero. To assess differences in accuracy, we determined the ratio of the sensitivity (or specificity) of HPV testing to that of repeat cytology for those studies where both test systems were evaluated on the same women and then pooled the individual ratios. The variation in accuracy measures in the individual studies and in the pooled measures were displayed graphically using forest plots (3739). Random-effects models were used for pooling accuracy parameters in cases of statistically significant interstudy heterogeneity (i.e., when P<.10 for Cochran's Q test) (40,41). In the absence of statistically significant heterogeneity, fixed models were used, with weighting of each individual study parameter according to the reciprocal of its variance (39). Meta-analyses were performed using the Stata statistical package (version 7.0; Stata Corp., College Station, TX) (42). Subgroup meta-analysis was used to assess the influence of study characteristics on the outcome. Age-stratified data on accuracy to detect CIN2+ were published in only one study (43). We also obtained age-stratified data from the ALTS directly from Dr. M. Schiffman (National Cancer Institute, Bethesda, MD) (33).
Publication Bias
Publication bias generally arises when smaller studies have a higher chance of being published if their results are positive. We assessed publication bias by using the asymmetry regression test and asymmetry plots, in which the normal deviate of the accuracy measure is plotted against its precision, which is related to the study size (44,45).
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RESULTS |
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Initially, we identified 29 potential articles for inclusion (18,19,2933,43,4666). However, we excluded 12 articles concerning triage of patients with ASCUS or LSIL, because the group with an ASCUS index smear could not be separated out (5566). In total, 17 articles reporting results of 15 studies met the inclusion criteria (18,19,2933,43,4654). Among the 15 studies, data allowing computation of the accuracy of repeat cytology at the thresholds ASCUS or worse, LSIL or worse, or HSIL or worse were obtained from nine, seven, and two studies, respectively. The characteristics of the included studies are summarized in Table 1 and Table 2.
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In total, 5454 women in the 15 included studies had ASCUS triage with HPV DNA testing. Nine studies were small, each contributing fewer than 200 women; four studies were of intermediate size, each contributing between 200 and 500 women; and two studies were large, each contributing more than 500 women. One of the large studies, the ALTS, contributed more than 2300 women (32,33).
Clinical Setting and Population Characteristics
For each study, patients were recruited from colposcopy clinics or from gynecologic services to which women had been referred because of a cytologic result of ASCUS. In four studies (48,51,53,54), the referred women had had repeated atypical cytology. Six studies (18,29,32,49,52,54) excluded women with a history of CIN, cervical surgery, or biopsy. One study (19) presented separate results for women with and without previous CIN. One study (31) included only women with ASCUS occurring after two sequential normal smears.
Blinding and Quality Review of Histologic Outcome
In six studies (18,29,43,47,49,52), it was explicitly stated that the histologic interpretation was blinded to the triage test results. In three studies (18,32,49), the histopathologic diagnosis was subjected to review by expert histologists.
Triage Tests
Several different HPV detection methods were used in the included studies. Two studies (46,47) used ViraPap and ViraType. These are two older commercial DNA dot blot test kits that use radioactive HPV RNA probes. The ViraPap contains a cocktail of seven probes that detect HPV types 6, 11, 16, 18, 31, 33, and 35. ViraType contains two distinct high-risk HPV cocktails that detect the high-risk HPV types 16, 18, 31, 33, and 35.
Hybrid Capture techniques were the most frequently used HPV DNA triage methods. The first generation Hybrid Capture I assay or Hybrid Capture Tube, which detects nine high-risk HPV types (i.e., 16, 18, 31, 33, 35, 45, 51, 52, and 56), was evaluated in five studies (18,19,29,48,51). The Hybrid Capture II assay, which contains a cocktail of probes that detect the same nine high-risk HPV types and HPV types 39, 58, 59, and 68 (67), was used in eight studies (31,32,43,49,50,5254). In one study (49), a prototype Hybrid Capture II assay was used that did not contain probes for HPV types 59 and 68. For all Hybrid Capture techniques, the hybridization yields a chemiluminescent signal that is compared with positive controls containing a known amount of HPV16 DNA. The detection limit is 10 pg of HPV DNA/mL in the Hybrid Capture I assay and 1 pg/mL in the Hybrid Capture II assay.
Cytology and Hybrid Capture II accuracy data from the same subjects were available in four studies (31,32,49,50). The conventional Pap smear was used as the cytologic triage method in most studies, although the ThinPREP liquid-based technique was used in two studies (32,49).
Triage by HPV Testing
The sensitivity to detect CIN2+ varied from extremely low, 26.7% with the ViraPap test (47), to 95.9% (32) and 100.0% (52) with the Hybrid Capture II assay (Table 3). The negative predictive values ranged from 88.7% (47) to 100.0% (52). The specificity ranged from 48.4% (32) to 97.1% (51). The positive predictive values ranged from 7.8% (19) to 90.6% (51). The prevalence of HPV positivity varied between 16.4% (46,48) and 56.8% (32).
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The numbers of true- and false-positive and true- and false-negative results for repeat cytology, defined at the cutoff ASCUS or worse, and derived parameters are shown in Table 4. Sensitivity ranged from 60.0% (46) to 85.0% (32), and specificity ranged from 44.7% (29,32) to 71.7% (50). Positive predictive values ranged from 3.8% (46) to 22.2% (47,50), and negative predictive values ranged from 93.4% (47) to 97.8% (46). The test positivity rate ranged from 32.4% (50) to 58.8% (32).
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The numbers of true- and false-positive and true- and false-negative results for repeat cytology, defined at the cutoff LSIL or worse, and derived parameters are shown in Table 4. Sensitivity ranged from 20.0% (29) to 59.2% (32), and specificity ranged from 77.9% (32) to 96.4% (46). Because of higher specificity in triaging at cutoff LSIL, the positive predictive value increased and ranged from 8.0% (29) to 32.5% (49). The negative predictive value ranged from 93.6% (32) to 98.2% (46). Test positivity was considerably lower than triage at cutoff ASCUS and varied between 4.7% (46) and 26.4% (32).
Triage by Repeat Cytology at Cutoff HSIL or Worse
Both studies (32,49) in which the accuracy of the repeat cytology was defined at the cutoff HSIL or worse had very low sensitivities (34.8% and 25.4%, respectively) and high specificities (96.8% and 99.2%, respectively).
Forest Plots
We created forest plots for the accuracy of all HPV tests combined (Fig. 1, upper panel) and for the Hybrid Capture II assay alone (Fig. 1, lower panel). Interstudy variation in sensitivity and specificity among all the HPV testing methods combined was large. The heterogeneity associated with the sensitivity of the Hybrid Capture II assay was much less than that for all HPV testing methods combined. Variation in the specificity of the Hybrid Capture II assay was reduced but was still substantial due to the low value observed in the ALTS study (32).
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We computed pooled estimates of the sensitivity and specificity (diamonds in Figs. 1 and 2) and of predictive values and likelihood ratios (Table 5). Meta-analysis including all HPV tests yielded a pooled sensitivity of 84.4% (95% CI = 77.6% to 91.1%) and a specificity of 72.9% (95% CI = 62.5% to 83.3%). Consideration of just the eight studies (31,32,43,49,50,5254) in which the Hybrid Capture II assay was used for the detection of high-risk HPV types yielded a sensitivity of 94.8% (95% CI = 92.7% to 96.9%) and a specificity of 67.3% (95% CI = 58.2% to 76.4%).
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The pooled ratio of the sensitivity of the Hybrid Capture II assay to the sensitivity of repeat cytology at cutoff ASCUS or worse, determined from four studies that evaluated both triage methods, was 1.16 (95% CI = 1.04 to 1.29), suggesting that the pooled sensitivity of the Hybrid Capture II assay was statistically significantly higher than that of repeat cytology at cutoff ASCUS or worse. The pooled specificity of the Hybrid Capture II assay was also higher, but the difference was not statistically significant (1.05, 95% CI = 0.96 to 1.15). Comparison of the Hybrid Capture II assay with repeat cytology at the respective cutoffs LSIL or worse and HSIL or worse yielded sensitivity ratios of 1.69 (95% CI = 1.54 to 1.85) and 2.80 (95% CI = 2.43 to 3.31), respectively, and specificity ratios of 0.71 (95% CI = 0.64 to 0.80) and 0.57 (95% CI = 0.44 to 0.74), respectively.
The negative likelihood ratio for the Hybrid Capture II assay was substantially lower than that for repeat cytology. The positive likelihood ratio for cytologic triage at cutoff LSIL or worse was substantially higher than that at cutoff ASCUS or worse because of its high specificity despite a low sensitivity. Both primary studies that provided data for cytologic triage at cutoff HSIL or worse (32,49) had extremely low sensitivity (meta-analysis data not shown).
The prevalence of CIN2+ ranged from 3% (46) to 36% (52), with a pooled mean of 10.5% (95% CI = 7.9% to 13.1%). Studies in which women with repeated atypia were evaluated had the highest prevalence of CIN2+ (52,53).
Influence of Study Characteristics
We determined the change in pooled sensitivity and specificity over technical and design variables for HPV DNA detection methods and repeat cytology at cutoff ASCUS or worse (Table 6). The sensitivity varied by viral test technique: it was low for ViraPap and ViraType (38.1%, 95% CI = 7.1% to 69.1%), higher for the Hybrid Capture I/Hybrid Capture Tube (78.8%, 95% CI = 67.0% to 90.5%), and even higher for the Hybrid Capture II assay (94.8%, 95% CI = 92.7% to 96.9%). The use of different HPV detection methods over time yielded a period effect for test sensitivity. The sensitivity of HPV DNA detection was also higher in studies in which a cervical broom or a conical brush was used for sample collection and in which the histologic outcome was submitted to quality review. There was no difference in sensitivity or specificity among cytologic triage subgroups.
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Publication Bias
We found a lower sensitivity for cytologic triage and a higher specificity for cytologic and virologic triage in smaller studies than in larger studies. This relation was, to a large extent, driven by the ALTS results (32,33), which include younger women. However, no asymmetry was found when odds ratios of accuracy for HPV triage and repeat cytology were considered. We conclude that the selective publication of smaller studies did not affect our main conclusions.
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DISCUSSION |
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Extent of Interstudy Heterogeneity
There was a wide range of sensitivities and specificities for cytologic triage. This was expected because the reproducibility of the cytologic interpretation of Pap smears is often reported as moderate to poor, especially for women with atypia or borderline disease (6870).
In the ALTS, only 32.4% of women with an original interpretation of ASCUS had a subsequent ASCUS result at enrollment, on average 2 months later (71). In the other studies, the proportion of women with ASCUS at index and enrollment smears varied from 17% (47) to 41% (29). The low reproducibility of cytology decreases the capacity to detect or to exclude intraepithelial disease and is likely to result in the variability in accuracy observed in the forest plots (Fig. 2). Accuracy varied even more for HPV triage methods than for cytology (Fig. 1), largely because of the use of different HPV DNA detection systems. It was therefore not recommended that they be combined into one pooled measure of HPV DNA testing. Nevertheless, it was useful to describe this variability among historical test systems, because we could clearly show that not all HPV DNA detection systems have the same accuracy. The sensitivity of the Hybrid Capture II assay showed low variability, reflecting the improved reliability of HPV DNA detection with the Hybrid Capture assay. Indeed, both the Hybrid Capture I and Hybrid Capture II assays have excellent reproducibility (unweighted kappa = 0.85 and 0.72, respectively) (19,72).
Specificity for the Hybrid Capture II assay was consistent across studies, with the only exception being that it was considerably lower in the ALTS. A possible explanation is that the majority of women in the ALTS belong to younger age groups in whom HPV infection may be common in the absence of cervical lesions (33,73).
Other HPV DNA Detection Methods
Certain authors applied additional HPV detection methods other than the Hybrid Capture assays. Morin et al. (31) used a polymerase chain reaction (PCR) amplifying a 450-base-pair sequence from the L1 region of the HPV genome, followed by a probe targeting 11 high-risk types. Compared with that of the Hybrid Capture II assay, the sensitivity of the PCR test to detect women with CIN2+ was equal (89.5% [95% CI = 66.9% to 98.7%]), but the specificity was substantially lower (59.0% [95% CI = 53.6% to 64.1%] for PCR versus 74.2% [95% CI = 69.2% to 78.8%] for the Hybrid Capture II assay). In a population of women with ASCUS or LSIL, Bergeron et al. (50) found a statistically nonsignificantly higher sensitivity for a PCR test that used MY9/11 HPV consensus primers (96%, 95% CI = 77% to 99%) than for the combined low- and high-risk probe of the Hybrid Capture II assay (86%, 95% CI = 65% to 97%), although the specificity for each test was similar (40% versus 41%). Bergeron et al. also used Southern blot hybridization to detect HPV, which was considerably more specific (65%, 95% CI = 60% to 71%) but also much less sensitive (46%, 95% CI = 24% to 68%) than PCR and the Hybrid Capture II assay. From Table 6, we conclude that certain HPV tests (ViraPap, ViraType, and Hybrid Capture I) cannot be recommended for triage of women with ASCUS. The performance of PCR-based systems is insufficiently documented in the ASCUS triage setting and needs further study.
Robustness of the Meta-analysis Results
This meta-analysis appears to corroborate the conclusions of the ALTS (32,33,74). However, from the forest plots (Figs. 1 and 2), the results from the ALTS are rather extreme. Sensitivity values were 85.0% and 59.2% for triage at cutoffs ASCUS or worse and LSIL or worse, respectively, in the ALTS, but 81.8% (95% CI = 73.5% to 84.3%) and 45.7% (95% CI = 34.0% to 57.4%), respectively, in our meta-analysis. The specificity was 44.7% for repeat cytology at the threshold of ASCUS or worse in the ALTS and 57.6% (95% CI = 49.5% to 65.7%) in our meta-analysis. The sensitivity of the Hybrid Capture II assay was 95.9% in the ALTS and 94.8% (95% CI = 92.7% to 96.9%) in our pooled data, and its specificity was 48.4% in the ALTS and 67.3% (95% CI = 58.2% to 76.4%) in our pooled data.
To investigate whether the difference in sensitivity between repeat cytology and Hybrid Capture II assay was influenced by the ALTS results, we repeated the meta-analysis excluding the ALTS results. A meta-analysis considering only three studies (31,49,50) resulted in a pooled sensitivity ratio of 1.18 (95% CI = 1.03 to 1.36) and a pooled specificity ratio of 1.03 (95% CI = 0.89 to 1.19). Thus, inclusion of the ALTS data did not influence the pooled relative accuracy values.
Verification Bias
Because colposcopy was performed on every woman, with the exception of those in the ALTS, there was no verification bias in our analysis. In the ALTS, results from women in the HPV arm were not verified if the Hybrid Capture II assay was negative, if results from repeat cytology ranged from normal to LSIL, or if no suspect macroscopic lesions were observed. However, colposcopy was performed on all women in a second arm of the ALTS. Because the detection rates of histologically confirmed CIN2+ were 11.3% (95% CI = 9.5% to 13.2%) for women in the colposcopy arm and 11.7% (95% CI = 9.9% to 13.7%) for women in the HPV arm, we conclude that there is no evidence of verification bias in the ALTS that could have potentially influenced our results.
Validity of the Gold Standard
We used colposcopy and histology as the gold standard test. An imperfect gold standard can influence the estimation of the sensitivity and specificity of a triage test, which can be assessed by examining the variation of accuracy by disease prevalence (75). However, the accuracy did not change substantially, even over wide ranges of disease prevalence (Table 6). The sensitivity was higher when the colposcopist was aware of the triage test results (for repeat cytology at cutoff ASCUS or worse: 81% if unmasked versus 73% if masked; for HPV triage: 88% if unmasked versus 79% if masked). Although this difference was not statistically significant, it suggests variability in the validity of the gold standard. The specificities were similar for masked and unmasked evaluations.
Low Specificity of All Triage Methods
The specificity of triage with the Hybrid Capture II assay or by repeat Pap smears at a low cytologic threshold was moderate to poor. Colposcopy of all triage-positive women generates considerable costs. Therefore, there is a need for more specific tests with high predictive value that allow for the identification of women at increased risk for cervical cancer. Nevertheless, a recent costeffectiveness simulation study of alternative scenarios for ASCUS management (76) indicated that Hybrid Capture II is more effective and cost-effective than repeat cytology. HPV DNA testing can be done on residual fluid if liquid-based cytology is performed or if an additional sample is collected with the first smear, both of which reduce costs. In contrast, repeat cytology requires multiple visits (77). When evaluating the costeffectiveness of HPV-based triage, it should be noted that the specificity of the test is highly age-dependent and that cost may therefore vary depending on the age of the population to be screened.
Cross-sectional Outcome: Detection of CIN2+
Our analysis was restricted to studies documenting accuracy of triage methods for the presence of moderate dysplasia or worse (CIN2+). In a subsequent study, we will assess triage considering severe dysplasia and carcinoma in situ (CIN3) as the outcome. CIN3+ may be a more relevant endpoint because its potential to regress spontaneously is more limited than in CIN2 (15,78,79).
Our meta-analysis was further restricted to cross-sectional outcomes in which sensitivity and specificity were measured against a simultaneously applied gold standard (colposcopically directed biopsy). Longitudinal studies are required to assess the possibility of detecting missed lesions by repeat cytology before invasive cancer occurs (80). The ALTS group recently published their longitudinal trial outcomes, defined in terms of cumulative incidence of histologic CIN3+ over a period of 2 years, in which all subjects were followed at 6-month intervals and finally submitted to a colposcopy/histology check-up (81). The longitudinal sensitivity of HPV DNA testing only at enrollment for cumulative CIN3+ was estimated to be 92.4% (95% CI = 88.7% to 95.2%). Testing ASCUS women only once with Hybrid Capture II required referral of 53.1% (95% CI = 51.4% to 54.8%) of women in the HPV triage arm. However, repeat cytology at every visit with a threshold of ASCUS would potentially detect 97.2% (95% CI = 94.1% to 100%) of the cumulative CIN3+ cases. This repeat cytology scenario would refer 73% (95% CI = 70.1% to 75.4%) of all women for colposcopy and would require multiple successive visits and cytologic examinations. Nevertheless, our meta-analysis of cross-sectional accuracy for CIN2+ is relevant because women with ASCUS require a follow-up decision and CIN2+ is the usual threshold for treatment.
Delineation of the Categories of Atypical Squamous Cells According to the 2001 Bethesda Reporting System
Our meta-analysis concerns women with a previous interpretation of ASCUS, such as that defined at the 1988 and 1991 Bethesda Workshops (35,82). In 2001, a new version of the Bethesda Reporting System for Cervical Cytology was adopted that proposed a change in the subdivision of the global ASCUS class from three to two classes: ASC-US (atypical squamous cells of undetermined significance) and ASC-H (atypical squamous cells, HSIL cannot be ruled out) (35,83). According to the new reporting system, the previous classification of atypical squamous cells favoring a benign reactive process (ASC-R) is now classified as negative for intraepithelial lesions or malignancy. The American Society for Colposcopy and Cervical Pathology has also recently updated its guidelines for the management of cervical cytologic abnormalities according to the new Bethesda terminology. Detection of high-risk HPV DNA was proposed as the first choice for triage of women with a liquid-based cytology result of ASC-US, whereas direct referral for colposcopic exploration is proposed as the optimal approach for women with ASC-H (84,85). ASC-H is estimated to account for approximately 5%10% of the ASC category (83,8688). In the ALTS, the prevalence of high-risk HPV types in the ASC-H group was 86%, and the proportion of women with ASC-H that contained CIN2+ was 41% (87). HPV triage is therefore redundant for women with ASC-H.
It is not clear to what extent the elimination of ASC-R from the equivocal neoplastic changes will modify the conclusions of our meta-analysis. ASC-R account for approximately 20%50% of all ASCUS results in U.S. women and a lower percentage in European women (8791). Because the prevalence of high-risk HPV types in ASC-R lesions is substantially lower than in other ASC lesions and because the positive predictive value of ASC-R for high-grade disease is minimal, HPV triage is probably not cost-effective for women with ASC-R results.
The accuracy of high-risk HPV DNA detection for triage of women with ASC results defined according to the 2001 Bethesda Reporting System guidelines is insufficiently documented. Nevertheless, we expect that restricting HPV triage to women with ASC-US will reduce the volume of HPV testing and considerably optimize its efficiency in the detection of women with CIN2+.
Recent Reviews and Meta-analyses
HPV triage has recently been reviewed (28,92,93). Cuzick et al. (28) concluded that the available evidence did not support recommending widespread HPV testing in primary screening but that limited use, such as in management of women with borderline results, might be suggested. In the 2002 update of the French guidelines for management of women with cytologic abnormalities (92), high-risk HPV DNA testing is recommended in triage of women with ASC-US. The Australian Medical Services Advisory Committee team reviewed literature regarding the management of women with low-grade epithelial abnormalities (LGEA) and concluded that there was insufficient evidence to support reimbursement for HPV triage of LGEA (93). The authors remarked that international data did not match the particular Australian cytologic reporting system and that throughout the cytologic literature different thresholds for triage tests and outcomes were used, which made pooling data difficult (93). However, no effort was made to pool data by separate test thresholds and histologic outcomes. The Australian LGEA category encompasses essentially low-grade squamous intraepithelial lesions. Our meta-analysis concerned the triage of women with ASCUS and not women with LSIL. However, in another systematic review (34) and also in the ALTS (33,94,95) it was found that HPV triage for LSIL had limited use because the test positivity rate was too high. Disparities between the Australian review and ours are likely the result of differences in the inclusion criteria for the index smear.
In conclusion, evidence is available indicating improved cross-sectional sensitivity of the Hybrid Capture II assay in comparison with the repeat Pap smear considered at cutoff ASCUS or worse for the outcome of high-grade CIN among women with equivocal cytologic results. The specificity of both triage methods is low. Cytologic triage of women with ASCUS that considers higher cytologic cutoffs yields unacceptably low sensitivity. We conclude that the Hybrid Capture II assay is a better triage method than repeat cytology for women with ASCUS.
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Manuscript received August 11, 2003; revised December 17, 2003; accepted December 23, 2003.
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