Atypical squamous cells of undetermined significance hpv negative

Key Points

Question  What are the long-term benefits and harms of human papillomavirus (HPV) testing among women with cytology showing atypical squamous cells of undetermined significance?

Findings  In this study after an abnormal screening cytology, 16.0% more cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) lesions were detected in women with HPV testing, and time to CIN3+ detection was much shorter. Biopsy rates were 55% higher, and loop electrosurgical excision procedure rates were 20% higher in those who underwent HPV testing, leading to higher CIN2+ and CIN3+ detection rates.

Meaning  Human papillomavirus testing after abnormal cytology results in earlier and more complete detection of high-grade CIN lesions but at the expense of more biopsies and loop electrosurgical excision procedures.

Importance  Little is known about the long-term yield of high-grade cervical intraepithelial neoplasia (CIN) and the influence on biopsy and treatment rates of human papillomavirus (HPV) triage of cytology showing atypical squamous cells of undetermined significance (hereafter ASC-US cytology).

Objective  To examine 5-year outcomes after ASC-US cytology with vs without HPV testing.

Design, Setting, and Participants  In this observational study, all cervical cytology and HPV testing reports from January 1, 2007, to December 31, 2012, were obtained for women throughout New Mexico and linked to pathology reports. The dates of the analysis were May 4, 2015, to January 13, 2017.

Main Outcomes and Measures  Influence of HPV testing on disease yield, time to histologically confirmed disease, and biopsy or loop electrosurgical excision procedure rates.

Results  A total of 457 317 women (mean [SD] age, 39.8 [12.5] years) with a screening test were recorded between 2008 and 2012, and 20 677 (4.5%) of the first cytology results per woman were reported as ASC-US. CIN grade 3 or more severe (CIN3+) lesions were detected in 2.49% of women with HPV testing vs 2.15% of women without HPV testing (P = .23). Time to CIN3+ detection was much shorter in those with HPV testing vs those without testing (median, 103 vs 393 days; P < .001). CIN grade 1 was detected in 11.6% of women with HPV testing vs 6.6% without testing (relative risk, 1.76; 95% CI, 1.56-2.00; P < .001). Loop electrosurgical excision procedure rates within 5 years were 20.0% higher in those who underwent HPV testing, resulting in more CIN2+ and CIN3+ detection.

Conclusions and Relevance  Human papillomavirus testing led to faster and more complete diagnosis of cervical disease, but 55.8% more biopsies and 20.0% more loop electrosurgical excision procedures were performed. In those tested, virtually all high-grade disease occurred in the 43.1% of women who were HPV positive, allowing clinical resources to be focused on women who need them most. These data provide essential information for cervical screening guidelines and public health policy.

There has been much interest in the use of human papillomavirus (HPV) testing to guide the management of women with low-grade cervical cytology test results. Many countries, including the United States, recommended reflex HPV testing after cytology showing atypical squamous cells of undetermined significance (hereafter ASC-US cytology). The American Society for Colposcopy and Cervical Pathology recommended reflex HPV testing for ASC-US cytology in women 25 years and older and repeat cytology for those aged 21 to 24 years.1 Immediate HPV reflex testing or 12-month repeat cytology was considered acceptable for both age groups. Although widely used for several years in the United States, where the cross-sectional predictive value of a positive HPV test result for cervical intraepithelial neoplasia grade 2 or more severe (CIN2+ or CIN3+) is well established,1,2 less is known about the longer-term influence of routine HPV triage on disease detection and clinical management.

Recently, our group documented the use of HPV testing in New Mexico and its influence on subsequent biopsies and repeat cytology and HPV tests.3 Briefly, that study found that HPV testing was used for approximately 80% of women aged 30 to 64 years with ASC-US cytology. In contrast, the use of HPV co-testing was still below 20% among women aged 30 to 64 years in 2012 but has recently been rapidly increasing. Human papillomavirus positivity in ASC-US was strongly age dependent, ranging from 72% at age 15 to 20 years to 22% at age 50 to 64 years.

Herein, we extend that work by examining the influence of HPV testing for women with ASC-US cytology on the detection of CIN2+ and CIN3+ in the 5 years after HPV testing. The following issues are addressed: (1) the influence of HPV triage on the 5-year rate of high-grade lesions, (2) how HPV testing affects the interval between an ASC-US screening cytology and the detection of histologically confirmed high-grade CIN, and (3) the extent to which HPV leads to overdetection and overtreatment of low-grade lesions destined to regress during the subsequent 5-year period.

The focus of this study was the histologic CIN outcome after an ASC-US cytology screening result during 2008 to 2012 among women aged 21 to 64 years. A screening cytology was defined as a cytology test that was not preceded by another cytology test within 300 days. The New Mexico HPV Pap Registry obtained statewide cervical cytology and HPV testing records from 9 laboratories in New Mexico and 9 out-of-state laboratories between January 1, 2007, and December 31, 2012. Pathology records for biopsy outcomes were obtained for an additional year (through December 31, 2013) to enable a minimum follow-up of 1 year. The dates of the analysis were May 4, 2015, to January 13, 2017. Tests were linked to women using probabilistic matching4 and augmented with manual reviews when linkage was uncertain.5 Screening intervals have increased over time and have been detailed previously.5 Any HPV test for high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) within 28 days of a screening cytology test was used to assign HPV test status (positive, negative, or not performed). This test could have been a co-test with cytology as part of primary screening or a reflex test as a result of ASC-US cytology. Almost all HPV testing (95.3%) through 2012 was performed with a modular system (Hybrid Capture 2; Qiagen). Histology results from cervical and endocervical specimens were used to assess the incidence of CIN1, CIN2, and CIN3 after screening. Ongoing evaluations of cervical screening (cytology and HPV testing), diagnosis, and treatment by the New Mexico HPV Pap Registry have been reviewed and approved under exempt status by the University of New Mexico Human Research Review Committee.

Time from the first screening ASC-US cytology to histologically confirmed disease was assessed using (1 minus) Kaplan-Meier methods to obtain cumulative incidence curves and incidence rate estimates (with 95% CIs) at 1, 3, and 5 years for CIN1, CIN1+, CIN2, CIN2+, and CIN3+ by age and HPV test status (all, HPV tested, HPV not tested, HPV positive, and HPV negative). If more than 1 lesion was detected within 6 months of the initial histologic finding, only the highest-grade lesion was counted, but the date of the first biopsy was used to determine the interval from the first ASC-US screening cytology, whereas if a subsequent higher-grade lesion was found after 6 months, both were counted. CIN1+ and CIN2+ were computed to allow estimates of CIN1 and CIN2 alone without subsequent higher-grade lesions (eg, CIN1 alone is the difference between CIN1+ and CIN2+ and similarly for CIN2 alone). Differences between subgroups (eg, HPV tested vs not tested or HPV positive vs negative) were based on relative risks (RRs) calculated using Kaplan-Meier estimates at years 1 and 5. The 95% CIs and significance levels for RRs were calculated using the delta method and a normal approximation for the log-transformed RR via a software program (R package “epitools”; R Foundation for Statistical Computing). Follow-up for CIN1 was censored after the detection of CIN2+, and follow-up for CIN2 was censored after the detection of CIN3+. Follow-up was also censored after a loop electrosurgical excision procedure (LEEP) or hysterectomy (but not biopsy) and at the end of the study follow-up on January 1, 2014. All statistical tests were computed using software programs (SAS, version 9.4; SAS Institute Inc or R, version 3.2.2; R Foundation for Statistical Computing).

A total of 457 317 women (mean [SD] age, 39.8 [12.5] years) with a screening test were recorded between 2008 and 2012, and 20 677 (4.5%) of the first cytology results per woman were reported as ASC-US. For women with ASC-US, the median time from the prior screening test was 28.3 months and was similar across age groups. The median potential follow-up time after an ASC-US screening cytology test was 57.2 months. Of the ASC-US screening cytology tests, 16 648 of 20 677 (80.5%) had an HPV test either as a co-test or as a triage test within 28 days of the cytology result. In the same period, 15.6% of those with normal cytology had a co-test,3 indicating that the remaining 64.9% overall (or 80.6% of those tested) had HPV for triage of their ASC-US cytology. Although co-testing increased from 5.2% in 2007 to 19.1% in 2012 of all screens,3 no difference in HPV use for ASC-US was seen across this period (range, 77.2%-82.5%; P for trend = .70). It was not possible to distinguish between co-testing and triage tests on an individual level. Also, no differences by age group were seen (range, 79.1%-81.9%; P for trend = .50). Of those that had an HPV test, 7179 (43.1%) were positive. Human papillomavirus positivity and high-grade histologic findings were strongly and inversely age dependent (eTable 1 in the Supplement). Of those with an ASC-US screening result, within the follow-up period, no abnormal histology was found in 17 551 (84.1% [5-year Kaplan-Meier estimate]), CIN1 without subsequent CIN2+ was found in 1969 (9.9%), CIN2 without subsequent CIN3+ was found in 705 (3.6%), and CIN3+ was found in 452 (2.4%) (Table 1). Further details by age, HPV status, and Kaplan-Meier estimates at 1, 3, and 5 years are listed in Table 1 and eTable 1 in the Supplement.

The 5-year estimated cumulative rate of CIN3 or more severe lesions (adenocarcinoma in situ or cancer) was 2.4% in women with ASC-US screening cytology (in 2.5% of women with HPV testing vs 2.2% of women without HPV testing), indicating that HPV testing led to a 15.8% overall increase in the detection of CIN3+ (RR, 1.16; 95% CI, 0.92-1.45; P = .23). Earlier detection was apparent when HPV testing was used (Table 1 and Figure), with a median time of 103 vs 393 days (P < .001), and was especially apparent in the first year of follow-up (Table 1, Table 2, and Figure), where the difference was 1.49% vs 0.93% (absolute difference, 0.56%) (RR, 1.60; 95% CI, 1.14-2.25; P = .004). However, the absolute and relative differences were smaller by year 5 (absolute difference, 0.34%) (RR, 1.16; 95% CI, 0.92-1.45; P = .23). Therefore, most CIN3+ lesions are persistent and are eventually detected even without HPV triage.

As with CIN3+, time to diagnosis of CIN2 was much shorter in women who had an HPV test (median, 91 days in those tested vs 340 days in those not tested; P < .001) (Table 1 and Figure). In particular, the rate after 1 year was 3.0% in those with HPV testing vs 1.6% in those without HPV testing (RR, 1.82; 95% CI, 1.41-2.35; P < .001). The major difference was seen within 1 year (6.87% vs 0.05%) (absolute difference, 6.82%) (RR, 128.52; 95% CI, 53.58-308.28; P < .001), but the absolute detection rate difference continued to diverge for the whole 5-year period (9.39% vs 0.52%) (absolute difference, 7.87%) (eTable 1 and eFigure 1 in the Supplement).

Slightly larger differences in 5-year detection rates were seen when the analysis was restricted to CIN2, where a 27.3% increase (4.3% of women with HPV testing vs 3.4% of women without HPV testing) in detection was seen in those tested (RR, 1.27; 95% CI, 1.06-1.53; P = .008) (Tables 1 and 2, Figure, and eFigure 2 in the Supplement), which led to a relative increase of 21.8% (6.3% of women with HPV testing vs 5.1% of women without HPV testing) for the detection of CIN2+ (RR, 1.22; 95% CI, 1.05-1.41; P = .007) (Table 2 and eFigure 3 in the Supplement). The detection of CIN3+ and CIN2+ after an ASC-US screening cytology was clearly age dependent, with lower rates observed at older ages both overall and in HPV-positive women (eTable 1, eFigure 3, and eFigure 4 in the Supplement). Differences were also observed between women aged 21 to 24 years and those aged 25 to 29 years (eFigure 5 and eFigure 6 in the Supplement).

Among women with HPV testing, the cases of CIN2 and CIN3+ disease diagnosed within 5 years were almost exclusively in HPV-positive women. The RRs were always above 10 except for CIN3+ in women aged 50 to 64 years, where it was 7.64 (eTable 2 and eFigure 4 in the Supplement).

CIN1 was detected within the subsequent 5 years in 11.6% of women with HPV testing and 6.6% of women without HPV testing, leading to a 76.2% increase in CIN1 detection (RR, 1.76; 95% CI, 1.56-2.00; P < .001) (Figure, Tables 1 and 2, and eFigure 1 in the Supplement). As summarized in Table 2, the increase was similar across age groups (P = .32). In those tested for HPV, CIN1 was much more common in women who were HPV positive (24.3% vs 2.7% after 5 years) (RR, 9.11; 95% CI, 8.01-10.36; P < .001) and was detected earlier (19.8% vs 0.8% after 1 year) (RR, 23.52; 95% CI, 18.81-29.41; P < .001), with a median time to detection of 61 vs 582 days (P < .001). The relative difference between HPV positive vs negative after 5 years was slightly smaller in women aged 21 to 29 years (RR, 6.54; 95% CI, 5.31-8.04; P < .001) but increased with age, and a test for trend was statistically significant (P = .002) (eTable 1 in the Supplement).

Five-year LEEP rates ranged from 76.6% for CIN3+ to 10.2% for CIN1 (Table 3). Five-year LEEP rates for CIN1 and CIN2 were lower in those who had HPV testing and similar for CIN3+, but the overall rate after 5 years was 20.0% higher in those who had HPV testing (4.9% of women with HPV testing vs 4.0% of women without HPV testing, P = .03) because more disease was found. Women who only had CIN1 that was not followed by a higher-grade lesion had lower 5-year LEEP rates than all CIN1 (6.8% vs 10.2%), which was not statistically significantly different across HPV groups. Women who were HPV tested had a higher LEEP rate in year 1 (2.9% of women with HPV testing vs 1.5% of women without HPV testing, P < .001) but had slightly lower rates in years 2 through 5 (1.9% of women with HPV testing vs 2.6% of women without HPV testing, P = .01). The difference was primarily due to the higher initial CIN1 rate in those tested for HPV (Table 1). Much of this increase followed subsequent higher-grade repeat cytology (ie, 6.5% ASC-US only, 9.2% low-grade squamous intraepithelial lesions, 15.7% atypical squamous cells [cannot exclude high-grade squamous intraepithelial lesions], and 37.4% high-grade squamous intraepithelial lesions). LEEP rates in women with CIN1 only over 5 years were not statistically significantly lower in those who were HPV tested vs those who were not tested (6.7% vs 7.6%, P = .70), and most of these cases were in women with more than 1 CIN1 biopsy. The ratio of LEEPs to CIN3+ lesions detected after 5 years was similar and not statistically different between the 2 groups (1.95 for those tested vs 1.88 for those not tested) (Tables 1 and 3). LEEP rates were lower for each histologic grade of disease in younger women compared with older women but were higher overall (5-year estimated rate, 5.7% in women aged 21-29 years vs 4.0% in women aged 30-64 years) due to more disease in younger women (eTable 3 in the Supplement).

The proportion of women with 1 or more procedures, including a biopsy or an endocervical curettage (excluding LEEP), was also higher for those with HPV testing. The estimated proportion with 1 or more biopsies in the subsequent 5 years was 32.1% vs 20.6% (P < .001) for those without testing (a 55.8% increase) (eTable 4 in the Supplement). Of women with HPV testing, the estimated biopsy proportions were 59.7% among those who were HPV positive vs 11.2% among those who were HPV negative (P < .001). These rates were similar across age groups except for lower rates in those aged 50 to 64 years.

The extent to which differences in outcomes were related to more follow-up and biopsies in women with HPV testing is summarized in eTable 5 in the Supplement. Of those with HPV testing, an estimated 15.9% had no evidence of any further follow-up after the initial ASC-US screening cytology and HPV test compared with 21.1% of those without HPV testing (P < .001) so that more disease was probably undetected in those without HPV testing, and there was little difference across age groups. Of women with HPV testing, the follow-up rate was strongly influenced by the outcome (10.6% with no follow-up after an HPV-positive result vs 20.0% with no follow-up after an HPV-negative result, P < .001). Because follow-up was more complete for the HPV-tested group, especially for those who were HPV positive with complete follow-up, the true difference in 5-year CIN3+ rates between those tested vs not tested could have been smaller than the 0.34% observed. Therefore, HPV testing leads not only to earlier disease detection but also to more disease CIN3+ detection due at least in part to more complete follow-up of HPV-positive women.

This study is the first comprehensive evaluation to date of the influence of HPV testing on the long-term outcome associated with ASC-US cytology. Such analyses are only possible when a system is in place to monitor cervical screening using both cytology and HPV testing with follow-up of histologic outcomes. The New Mexico HPV Pap Registry is the sole statewide program capable of providing this information in the United States. Such surveillance systems are essential if population screening for cervical cancer, as well as other cancers and diseases, is to fulfill its prophecy as a cost-effective approach to disease prevention.

It is clear from this study and elsewhere6,7 that almost all of the high-grade disease in women with ASC-US cytology is associated with HPV positivity and that HPV testing leads to earlier detection and treatment of disease. Over a 5-year follow-up, more CIN lesions of all grades are detected if HPV testing is used. The increase was small for CIN3+ and not statistically significant but was statistically significant for CIN2 and CIN1. A higher sensitivity of HPV triage for CIN2+ has also been reported in an overview8 but did not account for follow-up time. For CIN1, there is clearly overdiagnosis of lesions destined to regress, and extra repeat cytology, colposcopy, and biopsy occurred in these women in the present study. However, these procedures led to the detection of more high-grade disease, and the ratio of LEEPs to CIN3+ lesions was not increased by HPV testing. Among HPV-tested women, virtually all of these procedures were in HPV-positive women (10.4% vs 0.7%). Newer triage algorithms with greater specificity based on the use of HPV genotype,9 methylation status,10,11 and p16 expression12 may help to minimize these procedures, which is especially important for younger women of childbearing age. An excess of CIN2 and a small increase in CIN3+ were also observed in women with HPV testing, indicating that some high-grade lesions are detected, which may also be likely to regress with this approach. However, some of this excess in detection of high-grade disease may represent undetected disease due to the lower sensitivity of cytology without HPV triage, and these women may still harbor as yet undiagnosed precancerous and invasive lesions.

Because the use of HPV testing was not randomized in this observational study, it is possible that women not tested had a different risk of disease or their clinicians used different follow-up strategies after ASC-US. Although we could not detect any secular trend in the use of HPV triage or variation in the age distribution of those tested, it is possible that there are socioeconomic or other relevant differences in aspects of the health care facilities that have not been measured herein. In preliminary geospatial analyses, we have observed that clinics located in rural areas (vs urban) are less likely to use HPV testing, either as a co-test for all or as ASC-US triage. We also found that, even in urban areas, public health clinics and some federally qualified health centers had almost no HPV testing being performed during the study period, suggesting that some women with lower socioeconomic status may not be offered HPV testing, which is an area of ongoing study.

However, even if the lack of HPV triage is only a measurable marker for other factors determining detection rates and time to diagnosis, it still provides useful information that can help to improve the management of ASC-US cytology. Nevertheless, the main findings herein of a shorter time to disease detection, a higher detection rate of high-grade and low-grade lesions, and increased biopsy and LEEP rates in women who are HPV tested appear to be robust.

Approximately 3.5% of screen-detected cancers are from the initial follow-up of ASC-US cytology.13 Presently, we do not have data on the influence of HPV triage on this rate, but the similar 5-year detection rates for statistically significant lesions suggest that the effect will be small. While a model-based cost-effectiveness analysis has been conducted and suggested that HPV triage is more effective and less costly than repeat cytology or immediate colposcopy,14 a full economic evaluation of the costs and benefits of HPV triage based on a large cohort is desirable. The present study also highlights the enormous predictive value of HPV testing for women with ASC-US cytology because virtually all high-grade disease occurred in the 43.1% of women who were HPV positive, which allows colposcopy and related resources to be focused on women who need them most.

Accepted for Publication: March 8, 2017.

Corresponding Author: Cosette M. Wheeler, PhD, Department of Pathology, University of New Mexico Health Sciences Center, 1816 Sigma Chi Rd NE, Mail Stop Code MSC02-1670, Albuquerque, NM 87131 ().

Published Online: June 22, 2017. doi:10.1001/jamaoncol.2017.1040

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Author Contributions: Drs Cuzick and Lee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cuzick, Lee, Gage, Wheeler.

Acquisition, analysis, or interpretation of data: Cuzick, Myers, Lee, Shi, Hunt, Robertson, Wheeler.

Drafting of the manuscript: Cuzick, Myers, Robertson, Wheeler.

Critical revision of the manuscript for important intellectual content: Cuzick, Myers, Lee, Shi, Gage, Hunt, Wheeler.

Statistical analysis: Cuzick, Myers, Lee, Shi, Hunt.

Obtained funding: Wheeler.

Administrative, technical, or material support: Robertson, Wheeler.

Study supervision: Lee, Wheeler.

Conflict of Interest Disclosures: Dr Cuzick reports receiving personal income from advisory boards or speakers bureaus from Abbott, Becton Dickinson, Cepheid, Merck, and Trovagene and receiving grants to Queen Mary University of London from Abbott, Becton Dickinson, Cepheid, Hologic, OncoHealth, Qiagen, and Trovagene during the conduct of the study. Dr Wheeler reports receiving grants to the University of New Mexico from the US National Cancer Institute and the National Institute of Allergy and Infectious Diseases during the conduct of the study and receiving other support to the University of New Mexico from GSK, Merck, and Roche Molecular Systems outside of the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grant U54CA164336 (to Dr Wheeler) from the US National Cancer Institute–funded Population-Based Research Optimizing Screening Through Personalized Regimens (PROSPR) consortium. The overall aim of PROSPR is to conduct multisite, coordinated, transdisciplinary research to evaluate and improve cancer screening processes.

Role of the Funder/Sponsor: The funding sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Group Information: Members of the New Mexico HPV Pap Registry (NMHPVPR) Steering Committee reviewed the manuscript, gave input, and supported the concept and directions of the NMHPVPR, including the evaluations presented in this article. The NMHPVPR Steering Committee members participating in this effort were Nancy E. Joste, MD (University of New Mexico Health Sciences Center, Albuquerque, and Tricore Reference Laboratories, Albuquerque, New Mexico), Walter Kinney, MD (Kaiser Permanente Northern California, Sacramento), Cosette M. Wheeler, PhD (University of New Mexico Health Sciences Center, Albuquerque), William C. Hunt, MA (University of New Mexico Health Sciences Center, Albuquerque), Alan Waxman, MD, MPH (University of New Mexico Health Sciences Center, Albuquerque), Jane McGrath, MD (University of New Mexico Health Sciences Center, Albuquerque), Steven Jenison, MD (community member), Julia C. Gage, PhD, MPH (National Cancer Institute, Bethesda, Maryland), Mark Schiffman, MD, MPH (National Cancer Institute, Bethesda, Maryland), Philip E. Castle, PhD, MPH (Albert Einstein College of Medicine, Bronx, New York), Vicki Benard, PhD (Centers for Disease Control and Prevention, Atlanta, Georgia), Debbie Saslow, PhD (American Cancer Society, Atlanta, Georgia), Jane J. Kim, PhD (Harvard T. H. Chan School of Public Health, Boston, Massachusetts), Mark H. Stoler, MD (University of Virginia, Charlottesville), Jack Cuzick, PhD (Wolfson Institute of Preventive Medicine, London, England), Patti Gravitt, PhD (University of New Mexico, Albuquerque), Giovanna Rossi Pressley, MSc (Collective Action Strategies, Albuquerque, New Mexico), and Kevin English, RPh, MPH (Albuquerque Area Southwest Tribal Epidemiology Center, Albuquerque, New Mexico). No compensation was received for contributions to this article by any named authors or by the NMHPVPR Steering Committee members.

Additional Information: All data were reported to the New Mexico HPV Pap Registry under New Mexico Administrative Code (NMAC 7.4.3.).

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