Castle, Philip E. PhD, MPH1; Cox, J Thomas MD2; Schiffman, Mark MD, MPH1; Wheeler, Cosette M. PhD3; Solomon, Diane MD4
From the 1Divisions of Cancer Epidemiology and Genetics and 4Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; the 2Gynecology and Colposcopy Clinic Student Health Service, University of California, Santa Barbara, Santa Barbara, California; and the 3Departments of Molecular Genetics and Microbiology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, New Mexico.
Supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute. The ASCUS-LSIL Triage Study was supported by the National Cancer Institute, NIH, Department of Health and Human Services contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105. Some of the equipment and supplies used in these studies was donated or provided at reduced cost by Digene Corporation (Gaithersburg, MD), Cytyc Corporation (Marlborough, MA), National Testing Laboratories (Fenton, MO), DenVu (Tucson, AZ), BD Diagnostics-TriPath (Burlington, NC), and Roche Molecular Systems Inc. (Alameda, CA).
The authors thank the ALTS Group Investigators for their help in planning and conducting the trial and Information Management Services, Inc., Rockville, MD, for data management and programming support.
Corresponding author: Philip E. Castle, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Room 5004, MSC 7234, Bethesda, MD 20892-7234; e-mail: email@example.com.
Financial Disclosure Dr. Cox holds stock in Tigris Pharmaceuticals (Bonita Springs, FL), serves on the Scientific Advisory Board of Gen-Probe (San Diego, CA) and Diamics (Novato, CA), serves as a consultant to Graceway Pharmaceuticals (Bristol, TN), Takeda Pharmaceuticals (Deerfield, IL), BD Diagnostics-TriPath (Burlington, NC), Qiagen (Gaithersburg, MD), and JM Pharmaceuticals (West Deptford, NJ), serves on the HPV Vaccine Data and Safety Monitoring Board (DSMB) for Merck (Whitehouse Station, NJ), and serves on the speakers bureau for Qiagen and JM Pharmaceuticals. The other authors have no potential conflicts of interest to disclose.
Cytology read as high-grade squamous intraepithelial lesion (HSIL) are more likely to reflect histologic high-grade precancer (cervical intraepithelial neoplasia [CIN] grade 2 or 3) than cytology read as atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL). In most studies, CIN 2 or 3 is found in about 15% of women referred for the evaluation of ASC-US cytology, about 20% referred for LSIL, and about 70% referred for HSIL. However, the total number of cases of CIN 2 or 3 diagnosed after ASC-US and LSIL cytology is greater than that detected after HSIL cytology because of the numerical majority of these two milder cytologic interpretations.1
Because of the elevated risk of CIN 2 or 3 for women with HSIL cytology, previous guidelines generally have recommended an excision procedure when a precancerous lesion is not found on the colposcopic biopsy (“unconfirmed” HSIL).2 However, the 2006 American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for the management of unconfirmed HSIL have increased clinician and patient discretion in postcolposcopy management of young adult women by providing the option of either an excisional procedure or follow-up by repeat cytology and colposcopy at 6-month intervals for up to a year.3 Additionally, it is preferred to manage unconfirmed HSIL in adolescents by follow-up rather than excision. This change in the management of unconfirmed HSIL cytology is the outcome of increasing recognition that cervical excision procedures carry some risk for adverse pregnancy outcome4 and that cytologic HSIL and histologic CIN 2 in young women might represent acute infections that will resolve spontaneously.5
Unconfirmed HSIL presents clinicians with a management quandary, and it would be useful to better understand why some HSILs are not confirmed. To address these questions, we evaluated the 2-year risk of finding CIN 3 and early cancer among women participating in the ASCUS-LSIL Triage Study (ALTS) for community cytology of ASC-US or LSIL but found to have HSIL on repeat cytology at enrollment.
MATERIALS AND METHODS
ALTS (1997–2001) was a randomized trial comparing three management strategies for 5,060 women with ASC-US (n=3,488) or LSIL (n=1,572): 1) immediate colposcopy (referral to colposcopy regardless of enrollment test results), 2) human papillomavirus (HPV) triage (referral to colposcopy if enrollment HPV result by Hybrid Capture 2 (Digene Corporation, Gaithersburg, MD) was positive or missing or if the enrollment cytology was HSIL, or 3) conservative management (referral to colposcopy at enrollment if cytology was HSIL). ALTS involved four clinical centers: University of Alabama at Birmingham (Birmingham, AL), Magee-Womens Hospital of the University of Pittsburgh Medical Center Health System (Pittsburgh, PA), the University of Oklahoma (Oklahoma City, OK), and the University of Washington (Seattle, WA). The National Cancer Institute and local institutional review boards approved the study, and all participants provided written informed consent.
At the enrollment examination, all women underwent a pelvic examination with collection of two cervical specimens; the first specimen in PreservCyt for ThinPrep cytology (Cytyc Corporation, Marlborough, MA) and the second in specimen transport medium (Digene Corporation). Women in all three arms of the study were reevaluated by cytology every 6 months for 2 years and sent to colposcopy if cytology was HSIL. An exit examination with colposcopy was scheduled for all women, regardless of study arm or prior procedures, at the completion of the follow-up. Details on randomization, examination procedures, patient management, and laboratory and pathology methods have been published previously.6
Two HPV DNA tests were performed on clinical specimens collected at enrollment. Hybrid Capture 2 using probe set B, a pooled probe DNA test for one or more carcinogenic or high-risk HPV genotypes (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), was performed on PreservCyt specimens. A positive test does not identify which high-risk HPV genotype(s) are present. Hybrid Capture 2 is also well known to cross-react with HPV66, another high-risk genotype,7 and other low-risk HPV genotypes.8 Testing for 27 or 38 HPV genotypes was performed using an L1-based polymerase chain reaction (PCR) assay that employs a primer set designated PGMY09/11 (line blot assay) on the specimen transport medium specimen as previously described.9,10
We considered HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 as the primary high-risk HPV genotypes.7,11 Women were assigned to an HPV risk group based on the results of the two HPV tests and according to a priori established cervical cancer risk: 1) positive for HPV16, 2) positive for any other high-risk HPV genotypes and negative for HPV16 (high-risk HPV excluding HPV16), 3) positive for any low-risk HPV genotypes and negative for all high-risk genotypes, or 4) HPV-negative. In the case of discrepant HPV results between line blot assay and Hybrid Capture 2, we employed the following rules. Women who were negative by Hybrid Capture 2 but PCR-positive for high-risk HPV and women who were positive by Hybrid Capture 2 but PCR-negative for all HPV genotypes were classified as positive for high-risk HPV excluding HPV16. Women who were positive by Hybrid Capture 2 and PCR-negative for high-risk HPV genotypes but positive for low-risk HPV genotypes were classified as low-risk HPV because of the possibility that the Hybrid Capture 2 positive result was the consequence of cross-reactivity with low-risk HPV genotypes.12
Clinical management was based on the clinical center pathologists' cytologic and histologic diagnoses. A large portion of the cytology slides from follow-up were submitted for computer-assisted review (Neopath, TriPath Imaging, Burlington, NC). In addition, all referral smears, ThinPreps, and histology slides were sent to the Pathology Quality Control Group based at the Johns Hopkins Hospital for review and secondary diagnoses. Both pathology reviews were required to subcategorize HSIL cytology into the more severe HSIL-CIN 3 and the less severe HSIL-CIN 2, which for these analyses included any HSIL in which this distinction was not made (HSIL, not otherwise specified). For cytologic and histologic specimens, a Pathology Quality Control Group diagnosis of CIN 3 that had been called less than CIN 2 at the center triggered a safety notification sent by fax to the clinical centers. A diagnosis of CIN 2 or worse based on the clinical center pathology or a diagnosis of CIN 3 or worse based on the Pathology Quality Control Group review triggered treatment by loop electrosurgical excision procedure (LEEP). An exit examination with colposcopy was scheduled for all women, with loop electrosurgical excision offered for persistent low-grade lesions on CIN 2 or worse.
We used CIN 3 or worse diagnosed on biopsy or by LEEP by the Pathology Quality Control Group during the 2-year duration of ALTS as our primary outcome. This included four cases of cancer, all of which had their enrollment cytology called HSIL by both pathology groups.13 Exclusion of these cases did not appreciably change our results. We focused on 2-year cumulative absolute risk of CIN 3 or worse to account for the less-than-perfect sensitivity of a single colposcopic examination for detection of small, prevalent CIN 3 lesions.5,14 Because of the relevance to clinical practice, we also included the clinical center histologic diagnoses of CIN 2 or worse as an endpoint in some analyses.
We calculated the 2-year cumulative absolute risk of histologically confirmed CIN 3 or worse diagnosed by the Pathology Quality Control Group or histologically confirmed CIN 2 or worse diagnosed by the clinical center for any HSIL cytology and stratified on whether the HSIL cytology was called HSIL-CIN 2 or HSIL-CIN 3. For reference, we also calculated the risk for women with atypical squamous cells, cannot rule out HSIL (ASC-H; viewed as equivocal HSIL). We then evaluated the 2-year cumulative absolute risk of histologically confirmed CIN 3 or worse diagnosed by the Pathology Quality Control Group for HSIL, HSIL-CIN 2, and HSIL-CIN 3 cytology stratified on HPV risk group status. An extension of the Wilcoxon rank-sum test was used as a nonparametric test for trend across categories.15 We also examined the 2-year risk of CIN 3 or worse in subgroups of women with HSIL cytology stratified by enrollment colposcopic impression (less than low-grade or low-grade or worse), whether HPV16 was detected, and/or whether the cytology was confirmed as HSIL or at least ASC-H by the Pathology Quality Control Group.
To determine which factors were primarily responsible for finding CIN 3 or worse among women with HSIL cytology, we developed a multivariable model to evaluate the association of independent risk factors with 2-year cumulative CIN 3 or worse as diagnosed by the Pathology Quality Control Group. Contingency tables using Pearson χ2 tests were used to establish crude associations of risk factors with CIN 3 or worse. We then used multinomial logistic regression16 to calculate multivariable (adjusted) odds ratios and 95% confidence intervals (CIs) for CIN 3 or worse, with less than CIN 2 as the reference histologic outcome and CIN 2 kept as a distinct intermediate because it is an equivocal mixture of incipient CIN 3 with acute HPV infection by both high-risk and low-risk HPV.17 For clarity, we present only the associations with CIN 3 (compared with less than CIN 2).
Finally, we examined the crude associations of the timing of the CIN 3 (baseline or during follow-up/exit) with the number of biopsies taken at baseline whether the baseline cytologic impression was HSIL-CIN 2 or HSIL-CIN 3, HPV risk group, and colposcopic impression.
A P<.05 was considered statistically significant. Stata 8.2 (StataCorp LP, College Station, TX) was used for all statistical analyses.
Four hundred eleven of the 445 women (92.4%) with (repeat) enrollment cytology interpreted as HSIL by the clinical centers had complete disease ascertainment (403 had an exit visit with colposcopy; seven without an exit visit colposcopy had a clinical center histopathologic diagnosis of CIN 2 or worse, and one had a Pathology Quality Control Group histopathologic diagnosis of CIN 3 or worse, both of which led to a censoring treatment). The median age of the 411 women was 24 years (mean age 25.5 years). A description of the 411 women can be found in Table 1.
When comparing those included with those excluded, women referred because of ASC-US (compared with LSIL) were less likely to have complete disease ascertainment (P=.01), and there were minor differences between clinical centers (P=.02). Study arm, age at enrollment, HPV risk status, and a history of abnormal Pap tests were unrelated to inclusion in this analysis.
Of the 411 women with HSIL cytology included in the analysis, 354 (86.1%) had a cytologic interpretation of HSIL-CIN 2 and 57 (13.9%) had a cytologic interpretation of HSIL-CIN 3 (one clinical center read all 52 HSIL cytologic interpretations as HSIL-CIN 2). Another 110 women with equivocal HSIL (ASC-H) had complete disease ascertainment as described above. Almost all women (401 of 411, 97.6%) with a clinical center enrollment cytology of HSIL underwent a colposcopic evaluation during the enrollment period.
The 2-year cumulative risk of Pathology Quality Control Group–diagnosed CIN 3 or worse after an HSIL cytology was 47.4% (95% CI 42.5–52.4%) (Table 2); similar risk estimates were observed when clinical center–diagnosed CIN 3 or worse was used (data not shown). The 2-year cumulative risk of clinical center–diagnosed CIN 2 or worse after an HSIL cytology was 75.9% (95% CI 71.5–80.0%). The 2-year risks for CIN 3 or worse were greater for cytologic HSIL-CIN 3 than for cytologic HSIL-CIN 2 (73.7% compared with 43.2%, respectively, P<.001); nearly all HSIL-CIN 3 had a clinical center–diagnosed CIN 2 or worse within 2 years (98%, 95% CI 90.6–100%).
Among the 404 of the 411 women (98.3%) with HPV test results, there was a trend of increasing 2-year cumulative risk of Pathology Quality Control Group–diagnosed CIN 3 or worse with riskier HPV risk group (Ptrend<.001) (Table 3). The risk of CIN 3 was low when only a low-risk HPV genotype or no HPV was detected. This trend of increasing risk of CIN 3 or worse with riskier HPV risk group also was observed when stratified on whether the HSIL cytology was called HSIL-CIN 2 (Ptrend<.001) or HSIL-CIN 3 cytology (Ptrend=.03). Only one (1.9%) of 53 cases of HSIL-CIN 3 showed no HPV16 or other high-risk genotype compared with 25 (7.1%) of 351 cases of HSIL-CIN 2.
Figure 1 shows the trend of increasing 2-year absolute risk of Pathology Quality Control Group–diagnosed CIN 3 or worse among women with HSIL cytology with other indicators of risk. Women at the lowest risk of CIN 3 or worse (14.3%) were those who were HPV16-negative, had colposcopic impression of normal or metaplastic (ie, less than low-grade), and whose HSIL cytology was not confirmed as HSIL or at least ASC-H by the Pathology Quality Control Group (n=42, 10.2% of total). Women at the highest risk of CIN 3 or worse (82.4%) were those who were HPV16-positive, had colposcopic impression of low-grade and more severe, and whose HSIL cytology was read as HSIL or ASC-H by the Pathology Quality Control Group (n=74, 18% of the total). Similar patterns were observed using 2-year cumulative risk of clinical center pathology–diagnosed CIN 2 or worse as the endpoint, with the risk ranging from 52.4% for women with none of the risk factors to 98.7% for women with all three risk factors present (data not shown).
We then examined the factors associated with 2-year worst Pathology Quality Control Group diagnosis of CIN 3 or worse (compared with less than CIN 2) among women with HSIL cytology using a multivariable model (Table 4). The risk of having a CIN 3 or worse diagnosis was twofold to sixfold less likely for women with an HSIL cytology who 1) tested HPV-negative or positive for low-risk HPV (compared with testing positive for high-risk HPV excluding HPV16), 2) were from Centers 2 or 4 (compared with Center 1), and 3) were randomized into the HPV arm (compared with the immediate colposcopy arm) of the trial. The risk of having a CIN 3 or worse diagnosis was twofold to fourfold more likely for women with an HSIL cytology who 1) tested HPV16-positive (compared with testing positive for high-risk HPV excluding HPV16), 2) had HSIL-CIN 3 cytology (compared with HSIL-CIN 2), 3) were current smokers with four or more pack-years of use (compared with those who had never smoked), 4) had cytology confirmed as HSIL or ASC-H by the Pathology Quality Control Group (compared with not), or 5) had a colposcopic impression of low-grade or worse (compared with less than low-grade).
Finally, we examined the timing of the Pathology Quality Control Group diagnosis of CIN 3 or worse in the 401 (97.6%) women with an enrollment colposcopy. One hundred and seventy of the women with enrollment HSIL cytology (42.4%) were diagnosed with CIN 3 or worse at baseline (Table 5); 3.0% of women were diagnosed with CIN 3 or worse during follow-up visits, and 2.5% of women were diagnosed with CIN 3 or worse at exit.
All 42 women with HSIL-CIN 3 cytology and Pathology Quality Control Group–diagnosed CIN 3 or worse had their lesions detected at baseline, whereas only 83.3% with HSIL-CIN 2 and Pathology Quality Control Group–diagnosed CIN 3 or worse had their lesions detected at baseline (P=.003). Greater HPV risk groups also were associated with detection at baseline (Ptrend=.02). More than one biopsy (compared with one biopsy) (P=.2) and a colposcopic impression of low-grade or worse (compared with less than low-grade) (P=.2) were not significantly associated with the timing of diagnosis.
Women with HSIL-CIN 3 cytology had more biopsies taken during enrollment colposcopy than women with HSIL-CIN 2 cytology (Ptrend<.001). This tendency remained even when restricted to women who had at least one biopsy taken (P<.001). Women with HSIL-CIN 3 cytology were more likely to have a colposcopic impression of low-grade or worse (P=.001), which in turn was associated with having multiple (compared with one) biopsies taken (P<.001). Human papillomavirus risk group status was associated with HSIL-CIN 3 cytology compared with HSIL-CIN 2 (P<.001) but was not associated with number of biopsies taken in women with HSIL cytology (P=.6) or colposcopic impression (P=.5).
We evaluated cytologic interpretations of HSIL and the predictors of histologic confirmation in young women (mean age 25.5 years) participating in ALTS. The goal of the analysis was not only to quantify the risk of precancer associated with HSIL cytology but also to better understand predictors of “false positive” or “unconfirmed” HSIL cytology, ie, HSIL cytology in the absence of histologically confirmed precancer. On the other hand, there is the possibility of “false negative” histology, in which very small CIN 2 or even CIN 3 lesions are not found despite cytologic and virologic evidence.
As expected, there was a greater likelihood of histological CIN 3 with greater certainty (eg, confirmation) and severity of cytologic HSIL interpretation and/or the presence of other risk factors for cervical cancer. We observed a gradation of increasing 2-year cumulative risk of histological CIN 3 (increasing likelihood of histologic confirmation) from cytological ASC-H to HSIL-CIN 2 to HSIL-CIN 3. Although the distinction between HSIL-CIN 2 and HSIL-CIN 3 (made for research purposes only by the ALTS pathologists) is not required by The Bethesda System18 for classification of cytology and has not been demonstrated to be particularly reproducible (only 54.1% of the HSIL-CIN 3 interpreted by clinical center also was called HSIL-CIN 3 by the Pathology Quality Control Group, and 33.7% of the HSIL-CIN 3 interpreted by the Pathology Quality Control Group also was called HSIL-CIN 3 by the clinical center), the data nevertheless raise the question of whether such differentiation might be clinically useful. The new ASCCP Guidelines provide greater leeway for women with unconfirmed HSIL. If additional supporting clinical validation were to emerge, new guidelines might encourage differentiating HSIL, when possible, into HSIL-CIN 2 and HSIL-CIN 3 to provide a greater margin of safety in determining which cases of unconfirmed HSIL can be followed and which would be better managed by having an excisional procedure.
HPV16 detection was strongly associated with a CIN 3 or worse diagnosis among women with HSIL cytology. We infer from our data that when HPV genotype-specific testing becomes available, further delineation of risk will be advanced significantly. Women with unconfirmed HSIL cytology who test negative for HPV16 would appear to have the safest margin for postcolposcopy management by close follow-up, whereas those testing HPV16-positive are at significantly higher risk and may be best treated by having an excisional procedure.
We also anticipate based on these data that in HPV-vaccinated populations, primarily because HPV16 infection will be prevented, HSIL cytology will be less common and what remains will be less predictive of CIN 3. Given that the remaining precancerous lesions are caused by high-risk HPV genotypes that are less carcinogenic and therefore less likely to invade,19 watchful waiting for the management of HSIL cytology in younger, reproductive age women who have been vaccinated may be even more appropriate.
Some cases of apparently false-positive HSIL cytology were not in fact false-positive results but rather CIN 3 missed at initial colposcopy and found during intensive follow-up. Colposcopy is a visual tool that originally was not designed to detect the very small CIN 3 lesions that can underlie minor cytologic changes in well-screened populations.20 We found that colposcopists took more biopsies in those women with more definitive HSIL cytology (HSIL-CIN 3) and that this resulted in early detection of the precancer. The increase in the number of biopsies taken could have been prompted by the cytologic interpretation of HSIL-CIN 3 that raised clinician concern or because HSIL-CIN 3 cytology was an indicator of a larger cervical lesion visualized by colposcopy.
However, we note that among women with any enrollment HSIL cytology, colposcopic evaluation was more sensitive for the detection of precancerous lesions than the approximately 70% sensitivity reported for all women referred to colposcopy in the ALTS population.7 Almost 90% of all CIN 3 or worse diagnosed by the Pathology Quality Control Group (88.5%) and all CIN 2 or worse diagnosed by the clinical centers (87.5%) were detected at enrollment as the result of colposcopic evaluation, likely as a result of these lesions being more colposcopically apparent and heightened concern on the part of the colposcopist.
Women were referred into ALTS with a community ASC-US or LSIL cytology result and had a repeat cytology taken at enrollment. This study design increased the finding of HSIL cytology at enrollment in comparison with that found in a routine screening population (8.8% in ALTS compared with 0.7% in a recent U.S. review of screening cytology results).21 The ALTS subpopulation of women with enrollment HSIL cytology was also young, with 75% of women under the age of 28 (which is near the median age of CIN 3 diagnosis) and 95% under the age of 41 (approximate median age of early cancer). Thus, we also were analyzing earlier-detected, less-severe HSIL cytology than is typically found in a routine screening population. This undoubtedly led to a bias, possibly modifying risks typically observed for HSIL cytology found in routine screening of the entire general population. However, HSIL cytology results often are preceded by cytology interpreted as ASC-US or LSIL. Therefore, we do not believe our findings to be at odds with the findings for referral of HSIL cytology in routine clinical practice. We anticipate that the relative patterns of risk observed in this analysis are unlikely to be affected by the bias.
In conclusion, HSIL cytology is a highly specific indicator of histologic CIN 3 or at least CIN 2, especially in the context of an HPV16 infection. Forty-two percent of women with HSIL cytology had an immediate Pathology Quality Control Group diagnosis of CIN 3 or worse, and 68% had an immediate clinical center diagnosis of CIN 2 or worse; during follow-up, another 6% of women had a Pathology Quality Control Group diagnosis of CIN 3 or worse, and almost 10% had a clinical center diagnosis of CIN 2 or worse. Some false-positive HSIL does occur, and, when it occurs, it is found to be associated with testing HPV-negative or HPV-positive for low-risk HPV genotypes with greater uncertainty (unconfirmed as HSIL or ASC-H on review) and/or with less specific use (HSIL-CIN 2 compared with HSIL-CIN 3) of the HSIL cytologic interpretation. More studies are needed to confirm the possible clinical utility of distinguishing HSIL-CIN 2 from HSIL-CIN 3 and HPV16-negative from HPV16-positive HSIL cytology to guide management decisions. The distinction between HSIL-CIN 2 and HSIL-CIN 3 needs further validation. It will be important to show that watchful waiting of those with HSIL-CIN 2 and/or HPV16-negative HSIL is sufficiently safe against invasive cancer, which might be accomplished by large, retrospective studies of women who do not return immediately for colposcopy after HSIL cytology. Finally, with the advent of prophylactic vaccination against HPV16, the clinical meaning of HSIL cytology will need to be reconsidered because it will be less predictive of imminent precancer risk.
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