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Similar Risk Patterns After Cervical Screening in Two Large U.S. Populations: Implications for Clinical Guidelines

Gage, Julia C. PhD, MPH; Hunt, William C. MA; Schiffman, Mark MD, MPH; Katki, Hormuzd A. PhD; Cheung, Li A. MS; Myers, Orrin PhD; Cuzick, Jack PhD; Wentzensen, Nicolas MD, PhD; Kinney, Walter MD; Castle, Philip E. PhD, MPH; Wheeler, Cosette M. PhDfor The New Mexico HPV Pap Registry Steering Committee

doi: 10.1097/AOG.0000000000001721
Contents: Cervical Dysplasia: Original Research

OBJECTIVE: To compare the risks of histologic high-grade cervical intraepithelial neoplasia (CIN) or worse after different cervical cancer screening test results between two of the largest U.S. clinical practice research data sets.

METHODS: The New Mexico Human Papillomavirus (HPV) Pap Registry is a statewide registry representing a diverse population experiencing varied clinical practice delivery. Kaiser Permanente Northern California is a large integrated health care delivery system practicing routine HPV cotesting since 2003. In this retrospective cohort study, a logistic-Weibull survival model was used to estimate and compare the cumulative 3- and 5-year risks of histologic CIN 3 or worse among women aged 21–64 years screened in 2007–2011 in the New Mexico HPV Pap Registry and 2003–2013 in Kaiser Permanente Northern California. Results were stratified by age and baseline screening result: negative cytology, atypical squamous cells of undetermined significance (ASC-US) (with or without HPV triage), low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion.

RESULTS: There were 453,618 women in the New Mexico HPV Pap Registry and 1,307,528 women at Kaiser Permanente Northern California. The 5-year CIN 3 or worse risks were similar within screening results across populations: cytology negative (0.52% and 0.30%, respectively, P<.001), HPV-negative and ASC-US (0.72% and 0.49%, respectively, P=.5), ASC-US (3.4% and 3.4%, respectively, P=.8), HPV-positive and ASC-US (7.7% and 7.1%, respectively, P=.3), low-grade squamous intraepithelial lesion (6.5% and 5.4%, respectively, P=.009), and high-grade squamous intraepithelial lesion (53.1% and 50.4%, respectively, P=.2). Cervical intraepithelial neoplasia grade 2 or worse risks and 3-year risks had similar trends across populations. Age-stratified analyses showed more variability, especially among women aged younger than 30 years, but patterns of risk stratification were comparable.

CONCLUSION: Current U.S. cervical screening and management recommendations are based on comparative risks of histologic high-grade CIN after screening test results. The similar results from these two large cohorts from different real-life clinical practice settings support risk-based management thresholds across U.S. clinical populations and practice settings.

Supplemental Digital Content is Available in the Text.Results from two large cohorts from different clinical settings support risk-based management thresholds for cervical screening across U.S. clinical populations and practice settings.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Bethesda, Maryland; the Departments of Pathology, Internal Medicine, and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; Information Management Services Inc., Calverton, Maryland; the Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London, United Kingdom; the Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, California; and the Albert Einstein College of Medicine, New York, New York.

Corresponding author: Cosette M. Wheeler, PhD, Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, House of Prevention Epidemiology (HOPE), 1816 Sigma Chi Road NE, MSC02-1670, Albuquerque, NM 87131; e-mail: cwheeler@salud.unm.edu.

Supported by U54CA164336 (to C.M. Wheeler) from the U.S. National Cancer Institute-funded Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The overall aim of PROSPR is to conduct multisite, coordinated, transdisciplinary research to evaluate and improve cancer screening processes.

Financial Disclosure Dr. Schiffman and Dr. Gage have received HPV testing for research at no cost from Roche and BD. Dr. Cuzick has received research funding and reagents from Qiagen, Roche, GenProbe/Hologic, Abbott, BD, Cepheid, Genera, and Trovagene and has been personally compensated for Advisory Boards or Speakers Bureau activities from Trovagene, GenProbe/Hologic, Abbott, BD, Merck, and Cepheid. Dr. Wentzensen has received cervical cancer screening assays in-kind or at reduced cost from BD, Cepheid, Hologic, and Roche. Dr. Castle has received HPV tests and testing for research at a reduced or no cost from Qiagen and Roche, has been compensated for serving as a member on a Data and Safety Monitoring Board for Merck, and as a consultant for BD, Cepheid, Roche, GE Healthcare, ClearPath, Guided Therapeutics, and Gen-Probe/Hologic. Dr. Wheeler has received funding through the University of New Mexico from Merck and Co., Inc. and Glaxo SmithKline for human papillomavirus (HPV) vaccine studies and equipment and reagents from Roche Molecular Systems for HPV genotyping. The remaining authors did not report any potential conflicts of interest.

Presented at the American Association of Colposcopy and Cervical Pathology (ASCCP) Annual Meeting, April 13–16, 2016, New Orleans, Louisiana.

* For a list of members of the New Mexico HPV Pap Registry Group Authorship Steering Committee, see Appendix 1 online at http://links.lww.com/AOG/A881.

U.S. practice guidelines for cervical cancer screening and management are becoming increasingly complex as new tests become available.1–5 The latest cervical screening and management guidelines evaluate tests and determine appropriate management strategies by comparing the risk of precancer or cancer after each test result with a threshold risk that defines management.1,2 For example, colposcopy referral is recommended when the risk after a given screening or histology result is similar to or greater than the risk associated with a low-grade squamous intraepithelial lesion (LSIL) cytology result. Similarly, a return to routine screening is considered safe when the risk after a given test result is similar to or less than the risk associated with negative cervical cytology.

The current guidelines were based in large part on one source of data, namely, women undergoing cervical screening at Kaiser Permanente Northern California, a large integrated health delivery system that has practiced routine cytology and human papillomavirus (HPV) cotesting since 2003, yet the Kaiser Permanente Northern California practice setting does not necessarily reflect most parts of the U.S. medical system that include more diverse demographic characteristics, patient management, and laboratory methods and quality6–8; the generalizability of risk estimates could be questioned.

The New Mexico HPV Pap Registry provides a valuable comparison to Kaiser Permanente Northern California. The longitudinal data from the New Mexico HPV Pap Registry are derived from a heterogeneous population attending diverse health care settings. To investigate whether the risk estimates from Kaiser Permanente Northern California that informed current guidelines are generalizable, we compared the risks of cervical cancer and precancer for cytology and HPV results at the New Mexico HPV Pap Registry and Kaiser Permanente Northern California. Similar risk relationships across the large contrasting settings would provide supporting evidence for current and potentially future guidelines.

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MATERIALS AND METHODS

Established in 2006 as a statewide public health surveillance activity, the New Mexico HPV Pap Registry encompasses the screening and diagnostic cervical cancer screening services for residents across the entire state of New Mexico.9,10 The structure of the New Mexico HPV Pap Registry has been described previously.9 Under state regulation, laboratories must report to the New Mexico HPV Pap Registry all results of cervical cytology, cervical pathology, and HPV tests as well as vulvar and vaginal pathology performed on New Mexico residents.10 Cervical cytology and HPV results are routinely ascertained from nine laboratories in New Mexico and nine out-of-state laboratories that serve New Mexico residents. All hospitals and clinical practices in New Mexico report through these laboratories. Probabilistic matching and linking of different tests to a particular woman are performed and augmented by manual reviews when linkage is uncertain. Ongoing evaluations of cervical screening, 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. The National Institutes of Health Office of Human Subjects Research has similarly deemed this study exempt from institutional review board review because it does not contain personally identifiable information.

This analysis expands on an earlier, separate analysis of the New Mexico HPV Pap Registry data and therefore presents some risk estimations previously published.11 Women aged 21–64 years were included if their baseline cytology result was negative, atypical squamous cells of undetermined significance (ASC-US), LSIL, or high-grade squamous intraepithelial lesion (HSIL) reported during January 1, 2007 (when complete data collection started) through December 31, 2011. This analysis excluded women with baseline cytology results of atypical glandular cells, atypical squamous cells cannot rule out high-grade, or squamous cell carcinoma. Baseline is defined as the first screening result reported for a woman on or after January 1, 2007. Women were excluded if records indicated that they had a prior cervical cytology within 300 days of their baseline screening cytology (suggesting that the baseline test was a follow-up rather than screening test) or if they had a prior cervical excisional procedure reported to the New Mexico HPV Pap Registry (ie, loop electrosurgical excisional procedure or cone biopsy) or hysterectomy before their baseline screening cytology.9,12 Women with abnormal baseline cytology and no subsequent follow-up were excluded from all analyses.

Women were followed through electronic and paper medical records submitted to the New Mexico HPV Pap Registry.13 The outcomes were defined by local community readings of histopathology results from biopsy, endocervical curettage, an excisional procedure, or hysterectomy without central review from the date of baseline screening through December 31, 2013. A histologic outcome of cervical intraepithelial neoplasia (CIN) grade 2 or worse included results of CIN 1–2, CIN 2, CIN 2–3, CIN 3, carcinoma in situ, adenocarcinoma in situ, squamous cell carcinoma, and high-grade (not otherwise specified). An outcome of CIN 3 or worse included results of CIN 2–3, CIN 3, carcinoma in situ, adenocarcinoma in situ, and squamous cell carcinoma. Adenocarcinomas (n=154) were excluded from this report as a result of ongoing work related to potential misclassifications of cervical and endometrial adenocarcinomas. Follow-up for outcomes was terminated at the date of an excisional procedure or hysterectomy.

Kaiser Permanente is a nonprofit integrated health care system, which, as part of its mission, researches health outcomes within its membership. Under a data-sharing agreement with the National Cancer Institute, Kaiser Permanente Northern California shared aggregate data, stripped of personal identifying information, from its electronic medical records on cervical cytology results, HPV test results, and histopathology diagnoses. The Kaiser Permanente Northern California cohort consists of a longitudinal data set of more than 1 million women and is a large cohort, providing precise risk estimations. The Kaiser Permanente Northern California cervical screening program and our methods for risk calculation have been described previously.14,15 Women enrolled in Kaiser Permanente Northern California represent a generally well-screened population whose medical services are managed according to guidelines established by the Kaiser Permanente Medical Group. Most cytology specimens are processed and read at the Regional Laboratory, which benefits from intensive quality control. All HPV testing is performed using Hybrid Capture II at that same laboratory.

Briefly, women were aged 30–64 years undergoing HPV cotesting and women aged 21–29 years mainly undergoing cervical cytology testing with HPV triage of ASC-US, in the period of 2003 to June 2013. Cotesting was performed on two separate cocollected specimens with cervical cytology tests performed on the first of the two. Women were followed according to routine local practice: 1) women with HPV-positive and ASC-US cytology and LSIL or more severe results regardless of HPV status were referred to colposcopy; 2) HPV-negative and ASC-US cytology led to a recommendation of rescreening in 1 year; and 3) women aged 30–64 years who tested both HPV- and cervical cytology-negative (cotest-negative) were rescreened in 3 years; and women aged 21–29 years who tested cervical cytology negative were rescreened in 3 years.

For each woman aged 21–64 years undergoing cervical cancer screening in the period of 2003 to June 2013, we considered as the enrollment screen the first available cervical screening tests in the study period. Among women with an enrollment cervical cytology or HPV result, we excluded women with the following clinical history: previous excisional biopsy, hysterectomy or treatment, concurrent treatment or biopsy at the time of enrollment screen, previous diagnosis of CIN 2 or worse or HSIL or atypical squamous cells cannot rule out high-grade cytology, an immediately previous screening result that was HPV-positive or ASC-US or worse cytology, or a prior biopsy or cervical cytology test of any result within 300 days of enrollment screen (suggesting enrollment screen was a follow-up rather than screening test). Histologically confirmed cases of CIN 2, CIN 3, and cancer were ascertained from histopathology results of biopsies and excisional treatment through December 31, 2013.

Of note, cytology practice evolved at Kaiser Permanente Northern California during the 12 years of HPV cotesting. Conventional cytology was replaced by SurePath, prereview of slides by FocalPoint automated cytology readings was instituted, and beginning in 2007, HPV status was routinely revealed to cytologists.

The overall distribution of cytology screening results (normal, ASC-US, LSIL, and HSIL cytology plus ASC-US and HPV-positive and ASC-US and HPV-negative for HPV triage of ASC-US) was compared between the New Mexico HPV Pap Registry and Kaiser Permanente Northern California. The age-stratified distribution of screening results was also compared between cohorts with age categorized as: 21–24, 25–29, 30–39, 40–49, and 50–64 years. The age ranges of 21–24 and 25–29 years were chosen to show risks during ages for which there are different screening guidelines in the United States (ie, primary HPV screening is now recommended among women aged 25 years and older, whereas HPV testing from the start of screening at 21 to age 24 years is not recommended owing to high HPV prevalence and very rare cancer). The age-standardized distribution of screening results was calculated using the age distribution among females in the 2012 U.S. Census as a reference.

We calculated the cumulative incidence of histologic outcomes of CIN 2 or worse and CIN 3 or worse for each age grouping, screening result (defined previously), and age-stratified screening result using methods previously described.11,14,15 We concentrate on risk of CIN 3 or worse; CIN 2 or worse, a less reproducible and severe diagnosis of precancer, is included for completeness. Using a logistic-Weibull model, we calculated the cumulative risk as the sum of risk at the baseline cervical cytology (plotted at time zero on each figure) and the incidence after baseline. Risk estimates were compared and P values for statistical significance were calculated from 95% confidence intervals. This was a retrospective exploratory analysis. P values are given as nominal values and no adjustment for multiple comparisons has been made. All analyses were conducted using SAS 9.4.

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RESULTS

Overall, 456,519 and 1,313,128 women in the New Mexico HPV Pap Registry and Kaiser Permanente Northern California cohorts, respectively, had a baseline cervical cytology screening result. The distribution of cytologic abnormalities varied slightly between the cohorts with a slightly greater proportion of nonnormal cytology results in the New Mexico HPV Pap Registry (7.19%) compared with Kaiser Permanente Northern California (6.14%, P<.001) (Table 1). Among women with an ASC-US cervical cytology and concurrent HPV test for triage, HPV positivity was lower in the New Mexico HPV Pap Registry compared with Kaiser Permanente Northern California (41.0% of 15,724 women compared with 49.2% of 51,527 women, P<.001).

Table 1

Table 1

Women in the New Mexico HPV Pap Registry were younger than women in Kaiser Permanente Northern California (14.5% compared with 10.6% were aged 25–29 years; left column in Table 2; P<.001). Within some age groups, the distribution of abnormal baseline screening results varied between cohorts. Women aged 21–24 years in the New Mexico HPV Pap Registry were more likely to have abnormal baseline screening cytology results compared with women of a similar age in Kaiser Permanente Northern California (HSIL: 0.5% compared with 0.2%, respectively, P<.001; LSIL: 5.1% compared with 3.7%, respectively, P<.001). Women aged 25–29 years in the New Mexico HPV Pap Registry were also more likely to have abnormal baseline screening cytology results compared with women of a similar age in Kaiser Permanente Northern California (HSIL: 0.6% compared with 0.2%, respectively, P<.001; LSIL: 3.1% compared with 2.3%, respectively, P<.001).

Table 2-a

Table 2-a

Table 2-b

Table 2-b

The overall cumulative 3- and 5-year risks of CIN 2 or worse and CIN 3 or worse, regardless of baseline screening result, are presented in Table 3 with risks stratified by age. The numbers of cases are presented in Appendix 2, available online at http://links.lww.com/AOG/A881. Overall risks in the New Mexico HPV Pap Registry cohort were slightly higher compared with Kaiser Permanente Northern California (5-year CIN 3 or worse: 0.88% compared with 0.59%, respectively, P<.001). The age-stratified findings showed that the primary difference in risks was observed among women aged 21–24 years and 25–29 years in which women in the New Mexico HPV Pap Registry had a higher 5-year risk of CIN 3 or worse compared with women in Kaiser Permanente Northern California (age 21–24 years: 2.0% compared with 0.69%, respectively, P<.001 and age 25–29 years: 1.7% compared with 1.2%, respectively, P<.001).

Table 3

Table 3

Table 4 stratifies the 3- and 5-year CIN 2 or worse and CIN 3 or worse risks by baseline screening result and compares risks between the New Mexico HPV Pap Registry and Kaiser Permanente Northern California. The numbers of cases are presented in Appendix 2, http://links.lww.com/AOG/A881. For all screening results, the 5-year CIN 3 or worse risk estimates were close between the two cohorts with small differences among women with LSIL cytology (6.5% compared with 5.4%, respectively, P=.009), HPV and negative ASC-US (0.72% compared with 0.49%, respectively, P=.5), and cytology-negative (0.52% compared with 0.30%, respectively, P<.001).

Table 4

Table 4

The 5-year risks of CIN 3 or worse after baseline screening results stratified by age and referral cytology are presented in Figure 1 for the New Mexico HPV Pap Registry (solid line) and Kaiser Permanente Northern California (dotted line). The 5-year risks of CIN 2 or worse are presented in Appendix 3, available online at http://links.lww.com/AOG/A881. Across all age groups, the 5-year CIN 3 or worse risks showed a similar hierarchy for both cohorts: risks after an HSIL screening result were high (greater than 30%), risks after an HPV-positive and ASC-US result were medium and similar to those after an LSIL cytology result, and risks after an HPV-negative and ASC-US result were low and close to those of a cytology-negative result. Across screening results, differences in risk were observed between the New Mexico HPV Pap Registry and Kaiser Permanente Northern California for certain age groups. Among women aged 21–29 years, the 5-year CIN 3 or worse risks in the New Mexico HPV Pap Registry were higher than those in Kaiser Permanente Northern California for almost all baseline screening results. Among women aged 50–64 years, 5-year CIN 3 or worse risks were lower in the New Mexico HPV Pap Registry compared with Kaiser Permanente Northern California after LSIL (1.4% compared with 4.7%, P=.007).

Fig. 1

Fig. 1

In general, the risk relationships between cytology results and populations for 5-year CIN 2 or worse risks were similar to 5-year CIN 3 or worse risks and 3-year risks were similar to 5-year risks.

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DISCUSSION

The populations of the New Mexico HPV Pap Registry and Kaiser Permanente Northern California cohorts have slightly different immediate risks of cervical precancer (as estimated by the age-standardized prevalence of concurrent high-grade cytologic abnormalities at baseline screening) and risks of CIN 2 or worse and CIN 3 or worse histology within 3 and 5 years (slightly higher in the New Mexico HPV Pap Registry compared with Kaiser Permanente Northern California). Despite these differences, the cumulative risks after each screening result were similar across most age groups and similarly stratified women into risk bands of high risk (HSIL), medium risk (LSIL, HPV-positive, and ASC-US), low (ASC-US), and minimal risk (cytology-negative, HPV-negative, and ASC-US).

Human papillomavirus testing as a triage of ASC-US was useful as shown previously in studies worldwide.11,16,17 Human papillomavirus positivity among women with ASC-US cytology results was lower in the New Mexico HPV Pap Registry compared with Kaiser Permanente Northern California. Atypical squamous cells of undetermined significance was called slightly less often in Kaiser Permanente Northern California, perhaps because the standardized cytology practices (including knowledge of HPV status) at the Kaiser laboratories may affect ASC-US proportions and HPV positivity.

Women in the New Mexico HPV Pap Registry were younger and, compared with young women in Kaiser Permanente Northern California, the young women in the New Mexico HPV Pap Registry had higher risks of cervical precancer. Notably, although risks differed, the overall risk stratification patterns for baseline screening results within both groups of younger women were similar. The reason for this higher risk of cervical precancer among younger women in New Mexico is unclear but has been observed in other studies.18 It is possible that among young women, the risk of HPV infection might be higher in New Mexico compared with Kaiser Permanente Northern California, although this difference was not observed among women with ASC-US screening results.12 We had no information on known etiologic cofactors such as smoking, multiparity, and hormonal contraceptive use.

Risks of precancer declined as women aged.11,17,19 Although these trends might reflect a true decline of risk as women accumulate years of cervical cancer screening, they could also be an artifact of declining sensitivity of screening or colposcopic biopsy to detect cervical precancer as women age.20,21 Neither cohort has completely accounted for the prevalence of benign hysterectomy in the years after baseline screening.

Both the New Mexico HPV Pap Registry and Kaiser Permanente Northern California cohorts are from real-life clinical practices and are not a prospective study where women are systematically followed to ascertain disease status across standard multiple time points. Because women at Kaiser Permanente Northern California had HPV cotesting, those testing cytology-negative and HPV-positive (3.7% of women testing cytology-negative) have a repeat cotest in 1 year.16 Therefore, risk estimates for the first 3 years among women testing cytology-negative in Kaiser Permanente Northern California could be slightly higher than would be observed in New Mexico where HPV cotesting was only used in 19.1% of women aged 30–65 years attending for screening in 2012 (although it has more than tripled from 2007 to 2012).22

Overall, the cumulative risks after each screening result were remarkably close between the New Mexico HPV Pap Registry and Kaiser Permanente Northern California with the exception of the youngest and oldest ages. These differences in overall risks between the populations are likely explained by disparities in access to cervical cancer screening; approximately 29% of women aged 21–65 years in New Mexico were not screened for cervical cancer between 2008 and 2011 compared with much higher screening coverage in Kaiser Permanente Northern California.9

It was also assumed that risk estimates would vary by screening result between the New Mexico HPV Pap Registry and Kaiser Permanente Northern California because of the variability of clinical and laboratory practices. The New Mexico HPV Pap Registry represents a typical U.S. opportunistic screening scenario with diversity in health plans, clinical practice settings, and health care providers. By nature, the New Mexico HPV Pap Registry statewide setting includes great variability in patient management, pathology, and HPV laboratories with varying performance.23 Kaiser Permanente Northern California is a large integrated health care delivery system that follows screening and management guidelines established by Kaiser Permanente Medical Group.

The risk estimates after screening results that are reported from the New Mexico HPV Pap Registry and Kaiser Permanente Northern California cohorts are lower than those from other U.S. screening studies reporting higher CIN 2 or worse and CIN 3 or worse risks.24–26 This difference might be a result of study design because screening studies involve more rigorous follow-up including more frequent screening and colposcopy or the difference might represent different underlying risks within U.S. screening settings.

Although absolute risk estimates for given screening results likely do not apply across all settings, the overall risk stratification patterns in other U.S. settings are consistent. Reassuringly, screening and treatment algorithms based on cumulative risks of precancer or worse can apparently be applied across U.S. settings. Application to international settings with substantially different screening modalities and cervical cytology classification systems presents a greater challenge, although sometimes similar patterns might be observed.11

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Figure

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© 2016 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.