for the ALTS Group
Affiliations of authors: Division of Cancer Epidemiology and Genetics (PEC, MS) and Division of Cancer Prevention (DS), National Cancer Institute, NIH, DHHS, Bethesda, MD; Departments of Molecular Genetics and Microbiology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, NM (CMW)
Correspondence to: Philip E. Castle, PhD, MPH, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., MSC 7234, Bethesda, MD 20892-7234 (e-mail: castlep{at}mail.nih.gov).
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ABSTRACT |
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INTRODUCTION |
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In the United States, oncogenic HPV DNA testing (or "triage") for patients with ASCUS has proven to be a useful alternative to referring patients for immediate colposcopy (3) to detect CIN3 and cancer (collectively referred to as CIN3). Accordingly, HPV testing for a group of 13 oncogenic HPV types has now been approved in the United States for triage of patients with ASCUS cytology (911). In contrast, oncogenic HPV DNA testing is not informative for triage of patients with LSILs (5,12) because nearly all LSIL patients are HPV positive. However, an alternative triage strategy for LSILs might be useful because it would be valuable to distinguish women with underlying
CIN3 from the majority of women with LSILs who have HPV infections that probably will clear on their own.
Large, international caseseries and casecontrol studies have firmly established that approximately 50% of women with CIN3 have HPV16 (6,7,13). HPV16 is also the most common oncogenic HPV type among women in the general population, including women with ASCUS or LSILs. However, because of the lack of sufficiently large prospective studies, it has not been established how the absolute risk of
CIN3 differs by HPV16 status versus other oncogenic HPV types among women with equivocal or mildly abnormal cytology.
To examine this issue, we evaluated the 2-year cumulative absolute risks for CIN3 attributable to baseline-detected oncogenic HPV infection. Specifically, we determined the risks attributable to baseline-detected HPV16 and other oncogenic HPV infection for women enrolled into ALTS (ASCUS LSIL Triage Study) (12,14,15) because of an ASCUS or LSIL Pap smear.
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SUBJECTS AND METHODS |
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ALTS was a randomized, multicenter clinical trial that compared three management strategies for 5060 women (median age = 25 years, interquartile range = 2131 years, range = 1881 years) with ASCUS (n = 3488) or LSILs (n = 1572): immediate colposcopy (referral to colposcopy regardless of enrollment test results) (IC arm); HPV triage (referral to colposcopy if the enrollment HPV result was positive or missing or if the enrollment cytology was high-grade squamous intraepithelial lesion [HSIL]) (HPV arm); and conservative management (referral to colposcopy if cytology at enrollment or during follow-up was HSIL) (CM arm). Women in all arms of the study were reevaluated by cytology every 6 months for 2 years of follow-up. An exit examination, with colposcopy scheduled for all women regardless of arm or prior procedures, was performed at 2 years. Women with histologically confirmed lesions that were CIN2 or more severe were treated by a loop electrosurgical excision procedure. Details on randomization, examination procedures, patient management, and laboratory and pathology methods have been described previously (12,14,15). The National Cancer Institute and local institutional review boards approved the study, and all participants provided written informed consent.
HPV DNA Testing
Two HPV DNA tests were performed on clinical specimens collected at enrollment. Hybrid Capture 2 (HC2; Digene Corporation, Gaithersburg, MD) using probe set B, a pooled probe DNA test for one or more oncogenic HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), was performed on specimens from 4819 [95.2% of the 5060 women in ALTS (12,14,15)]; a positive test does not identify the specific HPV type(s). L1 consensus primer PGMY09/11 polymerase chain reaction (PCR) amplification and reverse-line blot hybridization for detection of 27 individual HPV genotypes (HPV6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 5159, 66, 68, 73 [PAP238A], 82 subtype [W13b], 83 [PAP291], and 84 [PAP155]) (16,17) were performed on separate specimens from 4915 (97.1%) patients. For 2833 of these patients (58%), we tested for an additional 11 individual nononcogenic HPV genotypes (61, 62, 64, 67, 6972, 81, 82 subtype [IS39], and 89 [CP6108]). Of the 5060 women enrolled into ALTS, 5052 (99.8%) women had at least one test result and 4682 (92.5%) had both test results. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 were considered the primary oncogenic HPV types (6) for this analysis.
Pathology and Treatment
Clinical management was based on the clinical center pathologists' cytologic and histologic diagnoses. In addition, all specimen slides were sent to the quality control pathology group (QC pathology), which was based at Johns Hopkins Hospital, for review and secondary diagnoses.
Statistical Analysis
We evaluated the 2-year absolute risk for histologically confirmed CIN3 (n = 542, including seven cancers) diagnosed by QC pathology with binomial exact 95% confidence intervals (CIs) as stratified by the referral cytology. We also analyzed data at a less stringent disease diagnosis of
CIN2 as rendered by the individual ALTS clinical center pathologists (n = 932), because
CIN2 is the treatment threshold for ALTS following typical U.S. practice (18). We evaluated cumulative risk at 2 years because all women had an exiting colposcopy for more complete disease ascertainment at 2 years; this endpoint allowed us to overcome any detection biases (19), missed prevalent disease (20), and/or differences between study arms.
Women were assigned a baseline HPV risk status according to the associations of HPV with cervical cancer (7): PCR positive for HPV16 (HPV16+); any oncogenic HPV type positive, excluding HPV16 (oncogenic HPV positive by PCR or by HC2 but PCR negative for HPV16) (HPV16/oncogenic HPV+); nononcogenic HPV positive (HC2 negative and PCR positive only for nononcogenic HPV types) (nononcogenic HPV+); and HPV negative (HPV). The order of risk, from highest to lowest, was HPV16+>HPV/oncogenic HPV+>nononcogenic HPV+>HPV. As a point of reference, we calculated the absolute risk of CIN2 and
CIN3 for any oncogenic HPV type, including HPV16 (oncogenic HPV+) as detected by PCR and/or by HC2. We separately evaluated the absolute risk for
CIN3 in women who were less than 30 years old and in women who were 30 years of age or older. The Pearson chi-square test was used to test for statistically significant differences (P<.05, two-sided) in absolute risk by age, by study arm, and by clinical center. Finally, we used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for
CIN3 associated with HPV risk status using combined HC2 and PCR data, referral Pap test interpretation, and age at enrollment, including interaction terms for HPV risk status and referral Pap test. Stata version 8.2 (Stata Corporation, College Station, TX) was used for all statistical analyses.
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RESULTS |
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Overall, women with ASCUS or LSIL cytology had 2-year cumulative absolute risks for CIN3 of 8.8% (95% CI = 7.9% to 9.8%) or 15.0% (95% CI = 13.3% to 16.9%), respectively (Table 1). Based on HC2 HPV testing of enrollment cervical specimens, oncogenic HPV+ women with ASCUS or LSILs had a 2-year absolute risk for
CIN3 of approximately 15% and 17%, respectively. HPV16/oncogenic HPV+ women with ASCUS or LSIL had 2-year absolute risks for
CIN3 of approximately 8% and 11%, respectively. HPV women with ASCUS or LSIL had 2-year absolute risks for
CIN3 of approximately 2% or 5%, respectively.
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For women with other individual HPV types, the 2-year absolute risks for CIN3 were lower; the risk in women with ASCUS ranged from 3.4% (HPV51) to 15.7% (HPV33), and the risk for women with LSILs ranged from 6.3% (HPV51) to 23.1% (HPV31). Among women positive for HPV18, the second most common type in cervical cancer, and negative for HPV16, the 2-year absolute risk of
CIN3 was 8.5% (95% CI = 4.3% to 14.7%) for those with ASCUS and 14.5% (95% CI = 9.1% to 21.5%) for those with LSILs, similar to the pooled risk for HPV16/oncogenic HPV+.
The 2-year absolute risks for CIN3 by HPV status did not differ statistically significantly by study arm. For example, HPV16+ women with ASCUS assigned to the IC, HPV, and CM arms had absolute risks of 27.3%, 35.3%, and 35.5% for
CIN3, respectively (P = .2). HPV16+ women with LSILs assigned to the IC, HPV, and CM arms had absolute risks of 40.6%, 38.0%, and 38.3% for
CIN3, respectively (P = .9). The absolute risks for CIN3 by HPV status also did not differ statistically significantly by clinical center (data not shown).
The 2-year absolute risk estimate for clinical centers' diagnoses of CIN2, the less stringent but clinically relevant endpoint for treatment (18), was 45.5% (95% CI = 41.1% to 50.0%) among HPV16+ women with ASCUS and 51.1% (95% CI = 45.5% to 56.6%) among HPV16+ women with LSILs. We observed no appreciable differences in absolute risk estimates when using QC pathology's diagnoses (versus the clinical centers') of
CIN2 as an endpoint (data not shown).
Women with ASCUS who were younger than 30 years of age had a higher 2-year absolute risk for CIN3 than did women 30 years and older who were PCR negative (risks = 2.9% versus 1.0%, P = .01), PCR positive for any HPV type (risks = 14.0% versus 9.6%, P = .01), or PCR positive for any nononcogenic HPV type (risks = 4.5% versus 0.7%, P = .03) (Table 2). Absolute risks for
CIN3 for LSIL-positive women were similar in both age groups.
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DISCUSSION |
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We observed an approximately 50% 2-year absolute risk of the clinically relevant CIN2 for HPV16+ women with LSILs. This is consistent with a previous study of 455 women that found a 62% 3-year absolute risk of
CIN2 for HPV16+ women with a mildly abnormal Pap smear (mild to severe dyskaryosis) (23).
The 2-year risk of CIN3 among women with non-HPV16 oncogenic types (HPV16/oncogenic HPV+) was similar to the risk attributable to having an ASCUS Pap smear without consideration of HPV status. For no other single HPV type did the risk of
CIN3 approach that associated with HPV16. Of note, six of the seven women (median age = 36 years) diagnosed as having cancer were HPV16+. Although a large proportion of
CIN3 was identified at baseline, 238 cases (44%) of
CIN3 (91 HPV16+ cases) were detected during the 2-year follow-up and included two follow-up cancer cases that were both HPV16+ at baseline and were probably baseline cancers first detected at follow-up (20). Thus, detection of HPV16 infection was the single most important risk factor for cancer and for missed
CIN3 in this population.
It should be noted that our precise estimates of absolute risk for combinations of cytology and HPV DNA testing are limited to the ALTS study population. Cytologic definitions of ASCUS of LSIL that include more severe cytology will probably result in greater risks associated with the different HPV risk strata. However, it seems unlikely that the relative importance of HPV risk strata will vary depending on the thresholds of cytologic interpretations. On the other hand, changes in the analytic sensitivity of HPV testing would probably affect both absolute and relative risk estimates by altering which women are identified as HPV positive. This connection between analytic sensitivity of an HPV test and the clinical performance is not linear. When analytic sensitivity is too low or too high, the risk estimates for cancer decrease (24). These limitations regarding the extension of ALTS results to other populations do not change the general findings, but they do suggest the need for realistic effectiveness research if HPV typing is added to current clinical protocols.
Our results did not differ statistically by study arm or by clinical center, which we infer to mean that these findings are independent of study design, are robust, and can be generalized. The cytologic interpretation of the referral Pap smear, ASCUS versus LSIL, was only weakly associated with the risk of CIN3. Thus, when calculating risk, it was far more informative to know a patient's HPV status than her cytologic ASCUS or LSIL interpretation.
It is noteworthy that women who were HPV negative by either HPV test had low, although nonzero, risk of CIN3 over 2 years and that women with either ASCUS or LSILs who were negative by both tests had an approximately 1% risk of
CIN3 over 2 years (data not shown). We suggest that this residual risk for precancer is attributable to failure of cervical cell sampling, false-negative test results, or incident disease. These data highlight that no test or combination of tests will provide perfect negative reassurance for cervical precancer or cancer.
We observed that the presence of nononcogenic HPV types increased the absolute risk of CIN2 compared with that in HPV-negative women, especially among women with ASCUS, but that the absolute risk for
CIN3 among nononcogenic HPV-infected women did not differ statistically from the risk among HPV-negative women.
We considered 13 types, HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, as the primary oncogenic HPV types (6) and other types to be nononcogenic. A recent report has suggested that other types might also be oncogenic (7). HPV53, an example of these potentially oncogenic types that we classified a priori as nononcogenic, was associated with only a 2.1% risk for CIN3 in the absence of other oncogenic HPV types.
Therefore, our data indirectly reinforce the impression that CIN2 is heterogeneous (i.e., a mixture of productive infections, even by nononcogenic types, and cancer precursors) and that although CIN2, as the clinical threshold for ablative treatment, provides a margin of safety, CIN3 more correctly represents true precancer.
The currently Food and Drug Administrationapproved HC2 test uses pooled probes for 13 oncogenic HPV types and does not distinguish individual types. Although it is useful for ASCUS triage, HC2 is not recommended for LSIL triage because the high proportion of positive results makes it uninformative. However, if the elevated risk of CIN3 in HPV16+ ASCUS or HPV16+ LSIL (30%40%) warrants more aggressive management (for example, immediate treatment in selected patients at risk of loss-to-follow-up), then separate HPV16 detection might be useful for the management of women with ASCUS or LSILs. A pooled-probe test and an HPV16 type-specific test could be performed concurrently or sequentially for ASCUS triage. A HPV16 type-specific test alone could be performed for LSIL "triage." In absolute numbers, women with HPV16+ ASCUS or LSILs represent a substantial number of patients, based on the frequency of these cytologic interpretations (2) and the prevalence of HPV16 within each cytologic category. From our data, approximately 500 000 women will have HPV16+ ASCUS or LSILs annually in the United States and may deserve more careful surveillance. Whether HPV16 (oncogenic HPV+) ASCUS or LSIL women can be safely managed less aggressively remains an important but unanswered clinical question.
In addition, among women who are diagnosed with less than CIN23 at colposcopy, knowledge of HPV16 status may have clinical utility in guiding postcolposcopy management by stratifying women according to their risk for subsequent high-grade cervical neoplasia. In ALTS, women with less than CIN2 at enrollment colposcopy but who were HPV16+ were far more likely to have a 2-year follow-up or exit diagnosis of CIN3 (14.3%) compared with women who were oncogenic HPV+ but HPV16 (7.2%) (P = .0005). Although the difference is modest, stratification by HPV16 detection better distinguishes risk than the histologic distinction between negative and CIN1 results from a colposcopically directed biopsy (20).
In the accompanying manuscript (25), we demonstrate in a screening population the potential utility of adjunctive testing for HPV16 and possibly HPV18 individually along with pooled probe tests for oncogenic HPV. Based on these data, we suggest that risk stratification using type-specific HPV16 detection (and perhaps HPV18 detection in screening) warrants further clinical, technical, and cost-effectiveness analyses.
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NOTES |
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Affiliations of the ALTS Group are as follows: National Cancer Institute, Bethesda MDD. Solomon, Project Officer; M. Schiffman, Co-Project Officer; S. Wacholder, Statistician; P. Castle; University of Alabama at Birmingham, ALE. E. Partridge, Principal Investigator; L. Kilgore, Co-Principal Investigator; S. Hester, Study Manager; University of Oklahoma, Oklahoma City, OKJ. L. Walker, Principal Investigator; G. A. Johnson, Co-Principal Investigator; A. Yadack, Study Manager; Magee-Womens Hospital of the University of Pittsburgh Medical Center Health System, Pittsburgh, PAR. S. Guido, Principal Investigator; K. McIntyre-Seltman, Co-Principal Investigator; R. P. Edwards, Investigator; J. Gruss, Study Manager; University of Washington, Seattle, WAN. B. Kiviat, Co-Principal Investigator; L. Koutsky, Co-Principal Investigator; C. Mao, Investigator; Colposcopy Quality Control GroupD. Ferris, Principal Investigator, Medical College of Georgia, Augusta, GA; J. T. Cox, Co-Investigator, University of California at Santa Barbara, Santa Barbara, CA; L. Burke, Co-Investigator, Beth Israel Deaconess Medical Center Hospital, Boston, MA; HPV Quality Control GroupC. M. Wheeler, Principal Investigator, University of New Mexico Health Sciences Center, Albuquerque, NM; C. Peyton-Goodall, Lab Manager, University of New Mexico Health Sciences Center, Albuquerque, NM; M. M. Manos, Co-Investigator, Kaiser Permanente, Oakland, CA; Pathology Quality Control GroupR. J. Kurman, Principal Investigator, Johns Hopkins Hospital, Baltimore, MD; D. L. Rosenthal, Co-Investigator, Johns Hopkins Hospital, Baltimore, MD; M. E. Sherman, Co-Investigator, The National Cancer Institute, Rockville, MD; M. H. Stoler, Co-Investigator, University of Virginia Health Science Center, Charlottesville, VA; Westat, Coordinating Unit, Rockville, MDJ. Rosenthal, Project Director; M. Dunn, Data Management Team Leader; J. Quarantillo, Senior Systems Analyst; D. Robinson, Clinical Center Coordinator; Quality of Life GroupDiane Harper, Dartmouth Medical School; Digene Corporation, Gaithersburg, MDA. T. Lorincz, Senior Scientific Officer; and Information Management Services, Inc., Silver Spring, MDB. Kramer, Senior Programmer/Analyst.
This study was supported by the National Cancer Institute, National Institutes of Health 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 this study were donated or provided at reduced cost by Digene Corporation, Gaithersburg, MD; Cytyc Corporation, Marlborough, MA; National Testing Laboratories, Fenton, MO; Denvu, Tucson, AZ; TriPath Imaging, Inc., Burlington, NC; and Roche Molecular Systems Inc., Alameda, CA.
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Manuscript received December 3, 2004; revised May 2, 2005; accepted June 13, 2005.
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