Obstetrics & Gynecology:
Original Research: Lead Article
Human Papillomavirus Triage for Young Women With Atypical Squamous Cells of Undetermined Significance
Wright, Jason D. MD; Rader, Janet S. MD; Davila, Rosa MD; Powell, Matthew A. MD; Mutch, David G. MD; Gao, Feng PhD; Gibb, Randall K. MD
From the 1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; 2Department of Pathology and Immunology; and 3Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri.
Corresponding author: Jason D. Wright, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes Hospital Plaza, Box 8064, St. Louis, MO 63110; e-mail: email@example.com.
OBJECTIVE: Human papillomavirus testing is a cost-effective strategy for the management of atypical squamous cells of undetermined significance. Young women have a high prevalence of transient human papillomavirus infections and low incidence high-grade cervical lesions, which may limit the usefulness of human papillomavirus testing in this cohort. We sought to estimate the usefulness of human papillomavirus testing for young women with atypical squamous cells of undetermined significance.
METHODS: A retrospective study of women with atypical squamous cells of undetermined significance was undertaken. Reflex human papillomavirus results and pathologic follow-up were evaluated. Age-stratified rates of human papillomavirus positivity, rates of high-grade dysplasia, and sensitivity and specificity were estimated.
RESULTS: A total of 1,290 women with atypical squamous cells of undetermined significance cytology were identified. The rate of human papillomavirus positivity decreased with age from 55% for those aged 25 years or younger to 12% for women aged older than 50 years (P < .001). The cumulative rate of high-grade lesions increased with age; 12% for patients aged 25 years or younger compared with 24% for women aged older than 50 years (P = .05). A negative human papillomavirus test more effectively excluded high-grade disease in the young women. No high-grade lesions were detected in the human papillomavirus negative women aged 25 years or younger compared with 3.8% of those aged older than 50 years (P = .04). The sensitivity for detection of high-grade disease was higher in women aged younger than 25 years compared with those aged older than 50 years (100% compared with 50%), whereas specificity was lower (14% compared with 44%).
CONCLUSION: Given the high prevalence of human papillomavirus and low occurrence of high-grade lesions in young women with atypical squamous cells of undetermined significance, a human papillomavirus–based triage strategy will result in the referral of a large number of women for colposcopy and may limit its cost-effectiveness.
LEVEL OF EVIDENCE: III
Of the 55 million Papanicolaou (Pap) tests performed annually in the United States, nearly 5% are interpreted as atypical squamous cells of undetermined significance (ASC-US).1 The ASC-US classification is used to designate cellular abnormalities that are suggestive, but not diagnostic, of a squamous intraepithelial lesion (SIL).2 Despite the revised classification system, the management of ASC-US cytology remains a clinical challenge. Even among expert cytopathologists the diagnosis is poorly reproducible.3 Studies have reported that from 3% to 36% of patients with ASC-US will have underlying cervical intraepithelial neoplasia (CIN) 2 or a more severe lesion.4 Finally, nearly 39% of women with histologically confirmed high-grade cervical lesions are identified through the evaluation of an ASC-US cytologic specimen.5
Given that human papillomavirus (HPV) is required for the development of cervical cancer, attention has focused on incorporating HPV testing into the management of ASC-US.6 The ASCUS-LSIL Triage Study was designed to compare prospectively 3 management strategies for ASC-US and low-grade squamous intraepithelial lesions (LSIL): HPV testing, immediate colposcopy, and repeat cytology. The study concluded that, for women with ASC-US, HPV triage was as sensitive as colposcopy for detecting CIN 3 and referred fewer women for colposcopic evaluation.1 A meta-analysis of 15 studies confirmed these findings.4 Despite the success of HPV testing, its value in young women is less clear. ASC-US cytology in young women and adolescents is associated with a high rate of HPV positivity but a low prevalence of high-grade cervical disease.7–9 In combination, these factors pose a potential limitation to HPV testing in young women with ASC-US.
To estimate the clinical usefulness of HPV testing for adolescents and young women with ASC-US cytology, we performed a retrospective of review of women with ASC-US who underwent reflex HPV testing. The primary objective of the study was to estimate whether HPV testing was clinically useful for young women with ASC-US. We estimated the rates of HPV positivity, the incidence of high-grade cervical dysplasia, and the sensitivity and specificity of HPV testing for young women and compared these results to older subjects. A secondary objective of the study was to examine the patterns of care for women with ASC-US to estimate whether age influenced how patients were evaluated and subsequently managed.
MATERIALS AND METHODS
Study approval was obtained from the Washington University School of Medicine Human Studies Committee. A review of the Department of Surgical Pathology cytopathology database was performed to identify all women with a cytologic sample interpreted as ASC-US. Subjects with specimens collected between January 27, 2003, and December 30, 2004, were included in the analysis. Only patients with a first cytologic diagnosis of ASC-US were evaluated. Subjects with ASC-H were excluded. The cytopathology and surgical pathology databases were queried to document all pathologic follow-up for each subject. Available cytology specimens, biopsies, conization specimens, endocervical curettings, and hysterectomy specimens were recorded.
All cytologic samples were liquid-based preparations. The cytologic specimens were reviewed and interpreted by a staff cytopathologist and reported using the 2001 Bethesda System terminology.2 Histologic specimens were processed in a routine fashion and interpreted by a staff pathologist. Standard definitions for cervical intraepithelial neoplasia and invasive cervical cancer were used.
Reflex HPV testing was performed from residual liquid-based cytology fluid using the Hybrid Capture 2 system (Digene Corporation, Gaithersburg, MD). Hybrid Capture 2 is a nucleic acid hybridization assay that detects 13 high-risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). The low-risk probe set was not used. Hybrid Capture 2 RNA probes specific for the HPV types listed above hybridize with viral DNA within the specimen. The hybrids are then bound and immobilized by antibodies bound to microplate wells. The hybrid complexes are then incubated with an alkaline phosphatase conjugated antibody. A chemiluminescent substrate is added, and the emitted light is recorded. A cutoff threshold of 1 pg of HPV DNA per milliliter of test solution was chosen to define a positive test. Human papillomavirus testing was performed by ARUP Laboratories, Salt Lake City, Utah.
For analysis, the patients were initially stratified by age and HPV status. The age strata were as follows: 25 years or younger, 26–40 years, 41–50 years, and older than 50 years. Multiple analyses were performed. To determine prevalent disease at the time of the initial ASC-US sample, the results of the first pathologic evaluation (cytology or histology) were recorded. A second analysis was performed to determine the outcomes of women who underwent histologic sampling within 1 year of the index ASC-US diagnosis. Finally, an analysis of the cumulative outcome of the patients was performed. For this analysis the most severe pathologic outcome during follow-up was recorded. Outcome data were dichotomized into categories of normal or low grade and high grade. This classification is based upon findings form the ASCUS-LSIL Triage Study trial in which the risk of subsequent high-grade disease in ASC-US patients was similar for women initially diagnosed with CIN 1 or negative findings.10 Lesions included in the normal or low grade category were: normal or benign pathology, ASC-US, atypical glandular cells of undetermined significance, LSIL and CIN 1. Lesions classified as high grade were high-grade squamous intraepithelial lesion (HSIL), CIN 2 and CIN 3, and invasive cancer. Sensitivity, specificity, and positive and negative predictive values were estimated using results from the first follow-up, histologic follow-up, and cumulative follow-up data.
Statistical analysis was performed using SAS 9.0 (SAS Institute Inc., Cary, NC). Patient characteristics and pathologic follow-up were summarized with counts and proportions. The distribution of items among the groups were compared with by χ2 and Fisher exact test as appropriate. Ninety-five percent confidence intervals were calculated for sensitivity, specificity, and positive and negative predictive values. A P value of < .05 was considered statistically significant.
A total of 1,290 women with ASC-US cytology were identified. The mean age of the cohort was 36 years and ranged from 13 to 91 years. Overall, 34% (438) of the samples were HPV positive, 62% (797) were HPV negative, and 4% (55) returned with equivocal results. Follow-up pathology (cytology or histology) was available for 845 (66%) patients. Women in the HPV-positive group were more likely to return for follow-up than HPV-negative patients (79% compared with 57%) (P < .001). The ASC-US patients were stratified by age into 4 groups: 25 years or younger, 26–40 years, 41–50 years, and older than 50 years. The percentage of women who were HPV positive decreased with advancing age (P < .001) (Table 1). Fifty-five percent (244) of women aged younger than 25 years with ASC-US tested HPV positive. The corresponding rates of HPV-positive ASC-US for the other age strata were 26–40 years (36%), 41–50 years (13%), and older than 50 years (12%).
Management of the ASC-US patients was analyzed after stratification by both age and HPV status (Table 2). For the HPV-positive subjects, the younger women were less likely to return for follow-up than the older women (P = .002). The method of evaluation of the ASC-US positive women was similar regardless of age. Cervical biopsies were performed at the first follow-up visit in 68% (123) of women aged 25 years or younger compared with 70% (21) of those older than 50 years (P = .21).
Among the ASC-US HPV-negative cohort, a smaller number of women aged 25 years or younger returned for follow-up (P = .006). This was most pronounced when the oldest strata, which had the highest rate of follow-up, was compared with the younger women. The method of evaluation for the HPV-negative ASC-US patients was comparable for all age groups. A histologic sample was obtained in 17–27% of the women in the 12 months after the index ASC-US diagnosis (P = .35).
Table 3 describes the cumulative pathologic outcomes of the cohort. The highest grade abnormality documented during follow-up was recorded for each individual. For analysis, outcome data were divided into 2 end points: normal or low grade and high grade (Table 4). A positive HPV test was associated with a lower rate of underlying high-grade disease in women aged 25 years or younger. At the first evaluation a high-grade lesion was found in 7% of women aged 25 years or younger, compared with 19% of those 26–40 years and 10% of patients older than 50 years(P = .18). This trend continued when patients evaluated histologically within 1 year after the incident ASC-US specimen were analyzed (P = .04). The difference for the HPV-positive women was most pronounced when the cumulative follow-up was analyzed; 12% of patients aged 25 years or younger and 24% of those aged 50 years or older had high-grade lesions identified (P = .05).
A negative HPV test reliably excluded high-grade cervical disease in young women. No high-grade lesions were identified in 12 months of follow-up in either women aged 25 years or younger or those aged 26–40 years with a negative HPV test. In contrast, high-grade disease was identified in the older, HPV-negative women. During cumulative follow-up, 9 noncervical, genital tract malignancies were found in women aged older than 50 years. These women were excluded from the analysis in Tables 4 and 5. At the time of first follow-up, 1.5% of the HPV negative, the cohort aged older than 50 years had high-grade lesions (P = .56) (Table 4). When women who underwent histologic sampling were examined, this increased to 17% (P = .03). Similarly, the cumulative rate of high-grade disease in the oldest age strata was 3.8% (P = .04).
The performance characteristics of HPV testing for ASC-US are shown in Table 5. Sensitivity was 100% (95% confidence interval [CI] 73–100%) and decreased with age to 50% (95% CI 11–89%) in the women aged older than 50 years. In contrast, specificity was lowest in the young women, 14% (95% CI 8–19%), and increased to 44% (95% CI 27–63%) in those aged older than 50 years. The positive predictive value was 9% (95% CI 4–14%) in women aged 25 years or younger compared with 21% (95% CI 6–46%) in those aged 41–50 years. These trends were similar when the analysis was performed using the data from cumulative follow-up (data not shown).
A subgroup analysis was performed to compare women aged 18 years or younger to those aged 19–21 years and 22–25 years (Table 6).The percentage of women who were HPV positive was similar and ranged from 53–59% (P = .67). High-grade disease was rare. None of the women who were aged 18 years or younger had a high-grade lesion identified either at the first evaluation or during the cumulative follow-up period. The sensitivity for detection of high-grade disease was 100% for all 3 groups, whereas specificity ranged from 13–16%.
We hypothesized that HPV testing for adolescents and young women with ASC-US cytology would be of limited clinical usefulness. This assumption was based on the knowledge that although young women have a high prevalence of transient, self-limited HPV infections and low-grade cytologic abnormalities, underlying high-grade dysplasia in this age group is relatively uncommon. The reported prevalence of HPV infection in young women is 14–46%.11–15 Concomitant with the increasing prevalence of HPV in this age group, the incidence of cytologic abnormalities has dramatically increased in young women over the past 3 decades. In adolescents the reported rates of ASC-US range from 7–16%, LSIL from 3–13%, and HSIL from 0.2–3%.16–21 Although cervical dysplasia is common in young women, cervical cancer is exceedingly rare. We previously reported the outcome of women aged 10–19 years with ASC-US cytology managed before the introduction of reflex HPV testing. The cumulative incidence of high-grade lesions (HSIL, CIN 2, or CIN 3) was 9%. Of note, no cases of invasive cancer were identified, and most of these preinvasive lesions regressed without ablative therapy.20 In a meta-analysis of 5,454 women of all ages with ASC-US cytology managed in HPV triage studies, the average prevalence of CIN 2 or greater was 10.5% but was reported as high as 36%.4 In the present cohort, high-grade cervical disease was found in 7% of women aged 25 years or younger at initial evaluation whereas the cumulative incidence of high-grade dysplasia was 12%. In contrast, similar lesions were found in 10% of women aged older than 50 years at first evaluation, and the cumulative incidence increased to 24%. Thus, although young women with ASC-US are at risk for harboring underlying high-grade disease, the prevalence of such lesions is clearly lower than in older women, and the risk of these lesions progressing similarly seems to be lower.
The role of HPV testing for the management of ASC-US is now well established.1,4 The prevalence of HPV positivity for patients with ASC-US varies from 16% to 59%.4 Among subjects with ASC-US, younger women are more likely to test positive for HPV.7–9,22–25 In an evaluation of 527 patients with ASC-US, 77% of those aged younger than 20 years were HPV positive compared with 58% of women older than 25 years.22 The high prevalence of HPV-positive ASC-US in young women results in referral of a large percentage of these patients for colposcopic examination.7–9 The large proportion of patients who undergo colposcopy is associated with a high sensitivity, but a relatively low specificity for detection of high-grade disease, given that the majority of these young women harbor low-grade lesions. Shay and colleagues8 estimated that HPV testing was associated with a sensitivity of 100% and a specificity of 57% for the detection of CIN 2–3 in women aged younger than 30 years. Forty-nine percent of the young women were referred to colposcopy. For women aged 30 years or older, the sensitivity dropped to 86%, with a specificity of 84% and a referral rate of only 20%. Similar findings were noted by Sarode et al7 in a program of HPV testing for ASC-US and LSIL. For women aged younger than 19 years the sensitivity and specificity for HPV testing were 100% and 13%, respectively. For subjects aged 30–39 years the sensitivity was 84%, whereas the specificity increased to 60%. In our population the rate of HPV-positive ASCUS was lower than in several of the previously reported studies (34% overall and 55% in women aged 25 years or younger). However, similar findings were observed; in the youngest age strata the sensitivity of viral testing was 100%, and the specificity was 14%. In women aged older than 50 years the sensitivity was 50% whereas the specificity was more than 3 times higher than in the young women, 44%. These trends suggest that HPV testing may be more appropriate in older women.9
Cost-effectiveness analyses have examined a number of management options for ASC-US cytology.26,27 In a comparison of HPV testing, repeat cytology, immediate colposcopy, and reclassification of ASC-US as normal, Kim and colleagues26 determined that reflex HPV testing provided the same life-expectancy benefits as the other strategies and was more cost-effective. However, the economic benefits of HPV testing may be abrogated in circumstances in which the majority of patients are HPV positive and require colposcopic evaluation.7–9,28 In an analysis of the ASCUS-LSIL Triage Study trial data, Sherman et al28 noted that HPV testing of women with ASC-US would result in colposcopic referral of 71% of women aged 18–22 years compared with only 31% of those aged 29 years or older. In addition to economic concerns, colposcopic examination of such a high percentage of young women has the potential to lead to identification and overtreatment of lesions that would naturally regress. These findings suggest that alternative management strategies for young women with ASC-US should be explored. A program of repeat cytology would select women with persistent cytologic abnormalities for colposcopy. The American Society for Colposcopy and Cervical Pathology currently endorses such a strategy for adolescents with LSIL.29 The benefits of these alternative management options must be weighed against the decreased sensitivity of repeat cytology and the low compliance of adolescents with cytologic follow-up.28,30
Our study has several limitations. First, follow-up was not available for a subset of patients. This pattern reflects the general trend of low compliance to follow-up for women with cervical dysplasia, particularly for young women.30 In addition, colposcopy with histologic sampling was not performed for all women in the HPV-positive cohort. A secondary objective of our study was to estimate the patterns of care of young women with ASC-US. The lack of histologic sampling performed in young women is a reflection of the current practice patterns for adolescents and young women with cervical dysplasia, at least at a single institution. Despite the lack of histologic sampling in all patients, the trends in sensitivity and specificity were similar whether we examined first follow-up, histologic follow-up, or cumulative follow-up.
In summary, there is an inverse relationship between age and HPV positivity for women with ASC-US cytology. Although young women with HPV are more likely to test HPV positive, they have a low incidence of high-grade cervical lesions at the time of diagnosis and during follow-up. The combination of a high prevalence of HPV and a low occurrence of high-grade lesions results in excellent sensitivity but poor specificity for HPV testing in young women with ASC-US. Management of these young women by HPV triage results in the referral of a large number of patients for colposcopy and may decrease the cost-effectiveness and clinical usefulness of this strategy in young patients. Further prospective data to evaluate alternate management strategies for adolescents and young women with ASC-US are clearly warranted.
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2. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114–9.
3. Stoler MH, Schiffman M, Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 2001;285:1500–5.
4. Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J. Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 2004;96:280–93.
5. Kinney WK, Manos MM, Hurley LB, Ransley JE. Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses. Obstet Gynecol 1998;91:973–6.
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7. Sarode VR, Werner C, Gander R, Foster B, Fulmer A, Saboorian MH, et al. Reflex human papillomavirus DNA testing on residual liquid-based (TPPT) cervical samples: focus on age-stratified clinical performance. Cancer 2003;99:149–55.
8. Shlay JC, Dunn T, Byers T, Baron AE, Douglas JM Jr. Prediction of cervical intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus testing in women with atypia on papanicolaou smears. Obstet Gynecol 2000;96:410–6.
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13. Bauer HM, Ting Y, Greer CE, Chambers JC, Tashiro CJ, Chimera J, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 1991;265:472–7.
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15. Ludicke F, Stalberg A, Vassilakos P, Major AL, Campana A. High- and intermediate-risk human papillomavirus infection in sexually active adolescent females. J Pediatr Adolesc Gynecol 2001;14:171–4.
16. Wright JD, Davila RM, Pinto KR, Merritt DF, Gibb RK, Rader JS, et al. Cervical dysplasia in adolescents. Obstet Gynecol 2005;106:115–20.
17. Simsir A, Brooks S, Cochran L, Bourquin P, Ioffe OB. Cervicovaginal smear abnormalities in sexually active adolescents: implications for management. Acta Cytol 2002;46:271–6.
18. Mount SL, Papillo JL. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics 1999;103:539–45.
19. Edelman M, Fox AS, Alderman EM, Neal W, Shapiro Silver EJ, et al. Cervical Papanicolaou smear abnormalities in inner city Bronx adolescents: prevalence, progression, and immune modifiers. Cancer 1999;87:184–9.
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21. Kahn JA, Goodman E, Slap GB, Huang B, Emans SJ. Intention to return for papanicolaou smears in adolescent girls and young women. Pediatrics 2001;108:333–41.
22. Boardman LA, Stanko C, Weitzen S, Sung CJ. Atypical squamous cells of undetermined significance: human papillomavirus testing in adolescents. Obstet Gynecol 2005;105:741–6.
23. Cox JT. Evaluating the role of HPV testing for women with equivocal Papanicolaou test findings. JAMA 1999;281:1645–7.
24. Rebello G, Hallam N, Smart G, Farquharson D, McCafferty J. Human papillomavirus testing and the management of women with mildly abnormal cervical smears: an observational study. BMJ 2001;322:893–4.
25. Eltoum IA, Chhieng DC, Roberson J, McMillon D, Partridge EE. Reflex human papilloma virus infection testing detects the same proportion of cervical intraepithelial neoplasia grade 2-3 in young versus elderly women. Cancer 2005;105:194–8.
26. Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance. JAMA 2002;287:2382–90.
27. Hughes AA, Glazner J, Barton P, Shlay JC. A cost-effectiveness analysis of four management strategies in the determination and follow-up of atypical squamous cells of undetermined significance. Diagn Cytopathol 2005;32:125–32.
28. Sherman ME, Schiffman M, Cox JT. Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study Group. Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst 2002;94:102–7.
29. Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. ASCCP-Sponsored Consensus Conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120–9.
30. Kahn JA, Goodman E, Huang B, Slap GB, Emans SJ. Predictors of Papanicolaou smear return in a hospital-based adolescent and young adult clinic. Obstet Gynecol 2003;101:490–9.
© 2006 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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