Monitoring and Ordering Practices for Human Papillomavirus in Cervical Cytology Findings From the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference Working Group 5 Christine N. Booth, MD; Christine Bashleben, MT(ASCP); Carol A. Filomena, MD; Marilee M. Means, PhD, SCT(ASCP); Patricia G. Wasserman, MD; Rhona J. Souers, MS; Michael R. Henry, MD

 Context.—The association of certain types of human papillomavirus with cervical carcinoma is well established. Human papillomavirus testing is now routinely used to screen for cervical carcinoma and precursor lesions of the cervix (cotesting and reflex testing) and these results are considered in patient triage and management. Objective.—To provide information about current laboratory practices in human papillomavirus testing and consensus best practice statements based on results from the College of American Pathologists’ laboratory-based survey funded by the Centers for Disease Control and Prevention. Design.—The College of American Pathologists submitted a paper-based survey to 1245 laboratories in the United States. After review of the initial results, follow-up Web-based survey results, and a literature review by an expert working group, consensus best practice statements were constructed by working group members for presentation at a national consensus conference. These best practice statements were discussed and then voted upon by conference participants.

Results.—A total of 525 laboratories responded to survey questions about human papillomavirus ordering and monitoring practices, whereas 546 responded to the overall survey. In most laboratories (87.6%), the high-risk human papillomavirus test is ordered as a reflex test by providers. A minority of laboratories (11.9%) routinely bundle low- and high-risk human papillomavirus tests. Most laboratories (84.4%) do not limit testing in patients with atypical squamous cells to women older than 20 years. More than half of laboratories (53.3%) monitor human papillomavirus positive rates in Papanicolaou tests with atypical squamous cells of undetermined significance. Conclusions.—It is not appropriate for laboratories to offer low-risk human papillomavirus testing for any clinical circumstance in gynecologic cytology. Laboratories should not order human papillomavirus testing to resolve diagnostic discrepancies. It is a valuable broad measure of laboratory quality to monitor the human papillomavirus– positive rates in Papanicolaou tests with atypical squamous cells. (Arch Pathol Lab Med. 2013;137:214–219; doi: 10.5858/ arpa.2012-0114-CP)

Accepted for publication June 19, 2012. From the Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio (Dr Booth); the College of American Pathologists, Northfield, Illinois (Mss Bashleben and Souers); Duke Raleigh Hospital and Duke University, Raleigh, North Carolina (Dr Filomena); the Cytotechnology Program, University of Kansas Medical Center, Kansas City (Dr Means); the Division of Cytopathology, North Shore–Long Island Jewish Health System, New Hyde Park, New York (Dr Wasserman); and the Department of Cytopathology, Division of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota (Dr Henry). The authors have no relevant financial interest in the products or companies described in this article. Supported in part from a contract (GS-10F-0261K) funded by the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry and are not intended to take the place of applicable laws or regulations. Reprints: Christine N. Booth, MD, Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Ave/L25, Cleveland, OH 44195 (e-mail: [email protected]).

T

214 Arch Pathol Lab Med—Vol 137, February 2013

he role of human papillomavirus (HPV) in cervical carcinogenesis was first discovered in the early 1980s. The first test to detect HPV became available in the mid1990s, well after gynecologic cytopathology quality measures were instituted as part of the Clinical Laboratory Improvement Amendments of 1988.1 Human papillomavirus testing continues to evolve in its use in gynecologic cytopathology in patient screening, triage, and management. Since 2004, cotesting for high-risk HPV (HR-HPV) in women older than 30 years at the time of the Papanicolaou (Pap) test became an accepted standard of care. Current clinical guidelines also recommend using HR-HPV test results to triage women older than 20 years with atypical squamous cells on a Pap test and postmenopausal women with low-grade squamous intraepithelial lesions (LSILs).2 Human papillomavirus testing is also used for patient follow-up for 1 year after colposcopy, 6 to 12 months postloop, and for follow-up of postcolposcopy patients with Pap tests with atypical glandular cells. HPV in Cervical Cytology––Booth et al

In order to determine current practices and create consensus best practice guidelines for quality assurance in gynecologic cytopathology, the College of American Pathologists (CAP), with funding from the Centers for Disease Control and Prevention, surveyed quality practices in cytopathology laboratories across the United States. Five working groups were charged to analyze data from the survey as well as compose additional questions for public comment posted on the CAP Web site. Our working group, working group 5, analyzed the results from the initial quality assurance survey and comments from the Web site to create consensus good laboratory practice statements that were considered and voted upon at the Gynecologic Cytopathology Quality Consensus Conference held in Rosemont, Illinois, in June 2011. Working group 5 addressed questions regarding HPV testing practices within the laboratory and the use of HR-HPV test results in the context of gynecologic cytology quality assurance. The purpose of this paper is to focus on laboratory use of HPV for clinical testing and as a component of quality monitoring in the cytopathology laboratory. The American Society for Colposcopy and Cervical Pathology (ASCCP) published 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.2 The 2006 ASCCP consensus guidelines provide revised evidence-based consensus guidelines for the management of women with abnormal cervical cancer screening test results, cervical intraepithelial neoplasia, or adenocarcinoma in situ.2 The ASCCP guidelines advocate analytic and clinical validation of HPV tests to ensure proven acceptable reproducibility, clinical sensitivity, specificity, and positive and negative predictive values for cervical cancer and verified precancer (cervical intraepithelial neoplasia, human papillomavirus/mild dysplasia [cervical intraepithelial neoplasia 2, 3]) as documented by Food and Drug Administration approval and/or publication in the peer-reviewed scientific literature. In these guidelines, it is recommended that HPV testing be restricted to high-risk (carcinogenic) HPV types (ie, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66). Testing for low-risk (noncarcinogenic) HPV types has no role in the evaluation of women with abnormal cervical cytologic results. In the 2006 ASCCP consensus guideline, ‘‘HPV testing’’ implies HR-HPV testing. The ASCCP guidelines address HPV in young females (by definition adolescent girls and women 20 years and younger). Given the low age-specific incidence of invasive cervical carcinoma in young females and the high prevalence of HR-HPV DNA in this population, reflex HPV testing of Pap tests with atypical squamous cells of undetermined significance (ASC-US) in young female patients has been deemed unacceptable. The reasoning for this guideline is that the vast majority of HR-HPV infections spontaneously clear within 2 years after initial infection and are of little long-term clinical significance. Human papillomavirus cotesting has not been deemed the standard of care in routine cervical cancer screening of females 29 years of age and younger.3 MATERIALS AND METHODS With the support of a grant from the Centers for Disease Control and Prevention, the CAP surveyed cytopathology laboratories in the United States on their quality practices in gynecologic cytopathology. The project components included (1) a pilot survey submitted to 10 laboratories, (2) a national paper-based survey Arch Pathol Lab Med—Vol 137, February 2013

submitted to all Clinical Laboratory Improvement Amendments– accredited laboratories and 54 laboratories identified from CAP proficiency testing enrollment and response to a notice from the CAP Web site, (3) follow-up Web-based questions based on the results of the paper survey, and (4) a consensus conference open to members of the general cytopathology community. The full details of the study process are published in another article in this issue.4 A working group consisting of cytopathology specialists, including expert cytotechnologists and cytopathologists, completed a review of the initial survey results. After review and discussion, the survey data were posted to the CAP Web site along with additional questions and space for public comment. The working group members completed a literature review and prepared consensus statements regarding good laboratory practices for consideration and voting at the Gynecologic Cytopathology Quality Consensus Conference on June 4, 2011. After initial presentation of the data and proposal of consensus best practice statements, conference participants voted on these statements. Each group’s presentation allowed time for open discussion including controversial topics in a second round of questions that were generated by the working group. This report summarizes the work of working group 5: Monitoring of HPV Rates. The other working groups present their findings in the series of other manuscripts included in this issue.

RESULTS Survey A total of 525 laboratories responded to a set of questions about HPV testing practices on the original 29-page paper survey sent to all Clinical Laboratory Improvement Amendments–certified laboratories in the United States. Not all of the laboratories responded to each question. In some cases, multiple responses to a single question were allowed. Human papillomavirus test ordering and reporting practices are shown in Table 1. Almost two-thirds of laboratories (61.9%) incorporate HPV test results into the Pap test report. In the majority of laboratories (87.6%), the HPV test for ASC-US interpretations is ordered as a reflex test by providers, and in a minority of laboratories (23.4%) it is ordered reflexively by the laboratory, independent of the provider’s order. Forty-one laboratories (7.9%) offer reflex HR-HPV testing in ASC-US for females younger than 21 years. Most laboratories do not limit ASC-US reflex testing to women older than 20 years (432 laboratories; 84.4% of respondents). In the laboratory volume analysis of HPV testing practices, smaller laboratories were more likely to reflexively order HPV testing independent of the initial order (P ¼ .001) and larger laboratories were more likely to order an HPV test with any squamous abnormality (P ¼ .001). The use of HPV test results within the context of the cytopathology laboratory’s quality assessment program was surveyed. Survey questions pertained to the use of monitoring HR-HPV rates within the laboratory, by cytotechnologist, by pathologist, and by Pap test diagnostic category. Tables 2 and 3 summarize these results. Follow-up Questions Posted on the Internet Bulletin Board Following review and analysis of the original survey data and literature review, working group members created 51 additional questions as an online survey and posted them on the Internet bulletin board on the CAP Web site. These questions were open ended and respondents were able to provide text answers and discussion. The online survey questions differed from the original paper survey because it was possible for several respondents from a single laboratory to reply. Up to 34 responses to each question HPV in Cervical Cytology––Booth et al 215

Table 1.

Human Papillomavirus (HPV) Test Ordering and Reporting Practices

How are HR-HPV tests for ASC-US ordered? (n ¼ 518)a Ordered as a reflex test by providers Ordered reflexively by the laboratory independent of the primary provider initial order Offered for reflex testing for females younger than 21 years of age Which HR-HPV tests are reflexively offered from a cytology specimen? (n ¼ 520)a ASC-US reflex ASC-H reflex AGC or other glandular abnormalities Pap test with any squamous abnormality LSIL with a Pap test regardless of age LSIL reflex in postmenopausal women Other None Pap test with NILM cases showing reactive or reparative changes Laboratory offers low-risk HPV testing (n ¼ 520) Never Only on request Routinely bundled with HR-HPV Other

No.

%

454 121 41

87.6 23.4 7.9

471 245 147 122 108 77 59 31 20

90.6 47.1 28.3 23.5 20.8 14.8 11.3 6.0 3.8

237 204 62 17

45.6 39.2 11.9 3.3

Abbreviations: AGC, atypical glandular cells; ASC-H, atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion; ASC-US, atypical squamous cells of undetermined significance; HR-HPV, high-risk HPV; LSIL, low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy; Pap, Papanicolaou. a Multiple responses allowed.

were received on the online survey. Each respondent was not required to answer each of the questions. The online survey confirmed that most laboratories perform HR-HPV testing on patients aged 20 years and younger at the clinician’s insistence. Just more than half of these laboratories will call these clinicians first to educate them about published guidelines before performing the HPV test. Some of these laboratories will include a comment in the final report that states that ‘‘modern guidelines do not recommend HPV tests for women 20 years of age and if obtained, the results should be ignored for management.’’ Only rare laboratories will refuse to perform a HR-HPV test in patients younger than 21 years despite a clinician’s insistence. Reasons stated for offering HR-HPV testing to patients aged 20 years or younger with ASC-US include clinician insistence, patient demands for the test, use of HPV results to resolve diagnostic dilemmas, and HPV test ordering out of habit on these patients. Some respondents indicated that they require clinicians who insist on HR-HPV tests in females aged 20 years or younger to submit a separately collected specimen directly to the virology laboratory. In the original paper survey, 47.1% of laboratories reported that they offer reflex HR-HPV testing in patients with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (SIL), cytologic results. Additional questions were posted online to the Internet bulletin board on the use of HPV testing in high-grade SIL patients. The responses were similar to the paper survey results. Knowledge of HPV test results in high-grade SIL were considered helpful in the following circumstances: (1) useful in older women with a negative history, (2) useful in pregnant women, (3) useful in resolution of diagnostic dilemmas with confidence, (4) useful in the clinician decision-making process regarding whether or not to proceed with a loop electrosurgical excision procedure, (5) useful in the triage of patients to routine follow-up when the HPV test is negative, and (6) useful in preventing colposcopic examination when the HPV test is negative. 216 Arch Pathol Lab Med—Vol 137, February 2013

The use of HPV test results for quality assessment within the cytopathology laboratory was further probed in the online survey posted to the Internet bulletin board. In the paper survey, only 28.8% of 513 laboratories reported that they compare HPV test results with ASC-US:SIL ratios for pathologist performance evaluation. The online survey further explored this practice and found that respondents did not compare HPV results with ASC-US:SIL ratios for pathologists because it was too complex to obtain data from the laboratory information system, because Pap test results and HPV results were in separate systems, or because even if pathologists were provided this information, it would not affect the pathologists’ sign-out tendencies. COMMENT Good Laboratory Practices: Consensus Statements, Consensus Voting Summary Results, and Comments Based on the survey results of current laboratory HPV testing practices, a comprehensive literature review of this topic, and the cytopathology working group member consensus, good practice laboratory statements were developed by working group members and presented to conference participants for voting and discussion. Controversial topics that required further discussion and clarification were re-presented to conference participants at the end Table 2.

Use of Human Papillomavirus (HPV) Test Results for Quality Assessment No.

HR-HPV rates are monitored to determine potential in accuracy of diagnoses ASC-US reflex HR-HPV results Yes 221 No 189 HPV DNA Results Yes 119 No 245

% trends 53.9 46.1 32.7 67.3

Abbreviations: ASC-US, atypical squamous cells of undetermined significance; HR-HPV, high risk human papillomavirus. HPV in Cervical Cytology––Booth et al

Table 3. Human Papillomavirus (HPV) Monitoring by Pap Test Result and Laboratory or Individual (n ¼ 392)a Laboratory Pap Test Result Total positive HR-HPV rate Positive HPV rates stratified by age ASC-US NILM LSIL HSIL ASC-H AGC Other None

No. 215 24 209 84 70 58 101 62 31 77

Cytotechnologist

Pathologist

%

No.

%

No.

%

54.8 6.1 53.3 21.4 17.9 14.8 25.8 15.8 7.9 19.6

46 3 54 23 17 13 25 11 6 90

11.7 0.8 13.8 5.9 4.3 3.3 6.4 2.8 1.5 23.0

62 1 84 23 23 18 35 20 7 94

15.8 0.3 21.4 5.9 5.9 4.6 8.9 5.1 1.8 24.0

Abbreviations: AGC, atypical glandular cells; ASC-H, atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion; ASC-US, atypical squamous cells of undetermined significance; HR-HPV, high-risk human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy; Pap, Papanicolaou. a Multiple responses allowed.

of the conference for additional discussion and a final vote. Following are the good laboratory practice statements developed by our working group with the questions and/ or statements that were voted upon by conference participants with voting results. 1. Laboratories should only offer HR-HPV testing for gynecologic cytology specimens. Laboratories should encourage clinicians to consider the latest consensus guidelines in ordering HR-HPV tests on gynecologic specimens. Laboratories should be cautious in using HPV test results to change or influence cytologic interpretations. From this good laboratory practice statement, questions and/or statements were developed for voting at the consensus conference. The following 3 questions and/or statements were posed to the conference participants in regard to this good laboratory practice statement: a. It is not appropriate to offer low-risk HPV testing on Pap tests for any clinical circumstance. There was moderately strong agreement (81%) with this statement by conference participants. Low-risk HPV (serotypes 6 and 11) is nononcogenic and often associated with genital warts, which clear spontaneously.5 When ordered with HRHPV, low-risk HPV is currently reimbursed at the same rate because it falls under the same Current Procedural Terminology code. This adds cost and may lead to inappropriate follow-up due to clinical confusion.6 b. Should HR-HPV tests be ordered by the laboratory to be used as a diagnostic test to aid in morphologic dilemmas and resolve diagnostic discrepancies? There was consensus agreement (75.8%) at the conference that laboratories should not order HR-HPV tests to resolve diagnostic discrepancies. High-risk HPV rates in women 30 years and older from the United States with normal Pap test results range from 4.0 to 9.0%.7,8 Thrall et al9 reviewed positive HR-HPV results in 146 women 30 years and older with negative Pap test results. Follow-up cytology and/or biopsy results in 120 of these women showed 3 high-grade lesions (cervical intraepithelial neoplasia 2 or 3); 17.5% of patients had low-grade lesions. Heider et al10 studied HR-HPV negative LSIL cases, stratified them by age, and found that only 3.7% of cases had high-grade dysplasia on follow-up. None of these patients were older than 50 years. The absence of cytologic abnormalities after careful screening should Arch Pathol Lab Med—Vol 137, February 2013

have precedence over HPV results to prevent unnecessary or overaggressive follow-up in these patients. c. High-risk HPV test results should aid in downgrading or upgrading of Pap test interpretations when available prior to sign-out. There was moderately strong agreement (83.9%) by conference participants that laboratories should not use HR-HPV test results to either downgrade or upgrade Pap test interpretations. 2. Although there is significant variability in interinstitutional HPV-positive rates in ASC-US Pap tests, monitoring the HPV-positive rate in ASC-US Pap tests is a valuable broad measure of quality. Performance beyond 2 standard deviations of the mean should prompt reassessment of diagnostic criteria used in the evaluation of Pap tests and/or investigation of the prevalence of HPV positivity in the population from which the Pap tests are obtained.11 The percentage of HR-HPV–positive ASC-US cases in conjunction with the ASC-US:SIL ratio can be used as a quality assurance tool within the laboratory. A high percentage of HR-HPV–positive ASCUS cases may indicate cytology overcalls of ASC-US on the basis of undercalling SIL. Conversely, with a low percentage of HR-HPV–positive ASC-US cases, the cytopathologist may be overcalling ASC-US by interpreting reactive/regenerative cellular changes as atypical.11,12 The following consensus conference statement pertains to the good laboratory practice statement above: ASC-US reflex HR-HPV results should be monitored to determine potential trends in accuracy of diagnoses. There was consensus agreement (71.9%) with this statement by conference attendees. 3. Monitoring the HPV-positive rate in other diagnostic categories such as LSIL and the comparison of these HRHPV rates with published benchmarks is also a valuable broad measure of quality for a laboratory and possibly for individuals. The following statement was posed to the conference participants: HR-HPV DNA results for other diagnostic categories should be monitored to determine potential trends in accuracy of diagnoses. To this statement, 50.8% of voters responded no, and consensus was not achieved. The ASC-US and LSIL Triage Study Trial sponsored by the HPV in Cervical Cytology––Booth et al 217

National Cancer Institute showed an overall HR-HPV rate of 82.9% in women with LSIL.13 Brismar-Wendel et al14 showed a slightly lower (71%) rate of HR-HPV in LSIL. These data also demonstrated that women with either ASCUS or LSIL after age 25 had similar HPV infectivity among age groups. Minor cytologic abnormalities still harbor HRHPV at a high rate, and continued monitoring of these women or catch-up vaccination may prevent further progression of the lesion. Ronco et al15 supported this in a previous study that supported HPV triage in women older than 35 years whether they had ASC-US or LSIL. More studies are needed to determine if minor cytologic abnormalities such as LSIL should undergo HR-HPV triage testing to stratify risk for developing a more serious lesion. 4. When possible, individual ASC-US:HR-HPV results should be compared with ASC-US:SIL ratios for pathologists to determine potential trends in overdiagnosis and underdiagnosis. The following statement was voted upon by conference participants: If possible, ASC-US/HR-HPV results should be compared with ASC-US:SIL ratios per pathologist as a general quality monitor. There was no consensus agreement with this statement (58.5% responded yes). Though laboratories may find it difficult to extract this information from the laboratory information system, and this may be a deterrent in monitoring this quality measure, the working group still recognizes this as a beneficial practice if the laboratory is able to extract the information.16,17 Following discussion during the first round of consensus statements and questions, it was clear that there were additional topics to be considered with regard to HPV testing practices within laboratories. Three additional questions and/or statements were discussed and voted upon by conference participants at the end of the conference: 1. Laboratories should routinely document all available HPV test results performed during the last 5 years preceding histopathologic diagnoses of cervical carcinoma, including laboratory site and date where each HPV test was performed. There was consensus agreement with this statement (69.6%). 2. Laboratories should routinely document all available HPV test results performed during the last 5 years preceding histopathologic diagnosis of cervical carcinoma, including both specific HPV test and platform and Food and Drug Administration–approved versus laboratory-developed test. There was moderately strong agreement among participants with this statement (80.8%). 3. Is it appropriate for a laboratory to order a HR-HPV test as a diagnostic test independent of the clinician? Conference participants responded no (84%) with moderately strong agreement. The ASCCP offers guidelines for appropriate use of HR-HPV testing as well as HPV genotyping. In addition, the clinician may have additional patient information that would render laboratory-ordered testing unnecessary. The patient may have HPV results from a different health system, or established squamous dysplasia on histology. Blind ordering of HPV would add unnecessary cost to the patient. 218 Arch Pathol Lab Med—Vol 137, February 2013

There are several strengths and weaknesses inherent in the process described herein. The strength of this process includes the sheer number of responding laboratories to the original survey, with 546 respondents providing a comprehensive inventory of quality assurance practices currently used in the United States in gynecologic cytopathology. Many of the consensus good quality practice statements developed by the working groups were directly derived from these data, were supported from the literature when available, and were vetted at the consensus conference. At the conference and within working groups, there was a great deal of sensitivity to the potential impact of these statements on the resources of cytopathology laboratories and possible regulations that could arise from the statements. These concerns prevented consensus and may result in a lack of adoption by laboratories. Reflective of the strengths and weaknesses of this process, there was an evolution in the development of the nomenclature regarding the term consensus good laboratory practice statements. This term represents a compromise between the term consensus guidelines at one extreme and the term consensus opinions at the other extreme. The former represents an extrapolation of the survey data, which were not, by the nature of the survey, strictly evidence based. The latter diminishes the significance of this massive collection of data. Although the reasoning behind each of the consensus good laboratory practice statements was presented at the consensus conference, many statements lacked clear-cut literature support. This was particularly true for areas such as agreement of cytotechnologist and pathologist diagnoses at time of initial sign-out by pathologist, a topic where there are scant published data. Where data were available, the literature was not graded on strength of evidence. Another potential concern was that many of the consensus conference attendees who were not members of a particular working group may not have been as familiar with the data as the presenters, potentially resulting in less well informed votes. Another problem with the analysis was the issue of laboratories with a relatively small volume of Pap tests, less than 1000 annually. It was unclear how the consensus good laboratory practices should be put into practice by these laboratories. Many of the suggestions offered in this series of papers for these laboratories are based on opinion, and represent an area ripe for future study. The consensus good laboratory practices presented in this series of papers represent a resource for laboratories to use to formally establish or to fine-tune their quality assurance program in gynecologic cytopathology. References 1. Clinical Laboratory Improvement Amendments of 1988. Final Rule. Fed Regist. 1992;57:7001–7186. Current CLIA regulations (including all changes through 01/24/2004). http://www.phppo.cdc.gov/clia/regs/toc.aspx. Accessed June 7, 2012. 2. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis. 2007;11(4):201–222. 3. Solomon D, Papillo J, Davis Davey D. Statement on HPV DNA test utilization. J Low Genit Tract Dis. 2009;13(3):135–136. 4. Tworek JA, Henry M, Jones BA. College of American Pathologists consensus conference on good laboratory practices in gynecologic cytology: background, rationale, and organization. Arch Pathol Lab Med. 2013;137(2): 158–163. 5. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132(2):277–284. 6. Moriarty AT. A rock and a hard place: HPV testing and financial gain. Diagn Cytopathol. 2007;35(8):463–464.

HPV in Cervical Cytology––Booth et al

7. Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Kinney W. Five-year experience of human papillomavirus DNA and Papanicolaou test cotesting. Obstet Gynecol. 2009;113(3):595–600. 8. Datta SD, Koutsky LA, Ratelle S, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003–2005. Ann Intern Med. 2008;148(7):493–500. 9. Thrall MJ, Russell DK, Facik MS, et al. High-risk HPV testing in women 30 years or older with negative Papanicolaou tests: initial clinical experience with 18-month follow-up. Am J Clin Pathol. 2010;133(6):894–898. 10. Heider A, Austin RM, Zhao C. HPV test results stratify risk for histopathologic follow-up findings of high-grade cervical intra-epithelial neoplasia in women with low-grade squamous intra-epithelial lesion Pap results. Acta Cytol. 2011;55(1):48–53. 11. Tworek JA, Jones BA, Raab S, Clary KM, Walsh MK. The value of monitoring human papillomavirus DNA results for Papanicolaou tests diagnosed as atypical squamous cells of undetermined significance: a College of American Pathologists Q-Probes study of 68 institutions. Arch Pathol Lab Med. 2007; 131(10):1525–1531.

12. Ko V, Nanji S, Tambouret RH, Wilbur DC. Testing for HPV as an objective measure for quality assurance in gynecologic cytology: positive rates in equivocal and abnormal specimens and comparison with the ASCUS to SIL ratio. Cancer. 2007;111(2):67–73. 13. Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst. 2001;93(4):293–299. 14. Brismar-Wendel S, Froberg M, Hjerpe A, Andersson S, Johansson B. Agespecific prevalence of HPV genotypes in cervical cytology samples with equivocal or low-grade lesions. Br J Cancer. 2009;101(3):511–517. 15. Ronco G, Cuzick J, Segnan N, et al. HPV triage for low grade (L-SIL) cytology is appropriate for women over 35 in mass cervical cancer screening using liquid based cytology. Eur J Cancer. 2007;43(3):476–480. 16. Nascimento AF, Cibas ES. The ASC/SIL ratio for cytopathologists as a quality control measure: a follow-up study. Am J Clin Pathol. 2007;128(4):653– 656. 17. Cibas ES, Zou KH, Crum CP, Kuo F. Using the rate of positive high-risk HPV test results for ASC-US together with the ASC-US/SIL ratio in evaluating the performance of cytopathologists. Am J Clin Pathol. 2008;129(1):97–101.

CAP ’13 Abstract Program Accepting Submissions Abstract and case study submissions will be accepted beginning Monday, February 4, 2013 for the College of American Pathologists (CAP) 2013 meeting. CAP ’13 will be held October 13 through the 16th in Orlando, Florida. Submissions for the CAP ’13 Abstract Program will be accepted through Monday, April 1, 2013. Accepted submissions will appear in the October 2013 issue of the Archives of Pathology & Laboratory Medicine. Visit the CAP ’13 website at www.cap.org/cap13 for a link to the submission site and additional abstract program information as it becomes available.

Arch Pathol Lab Med—Vol 137, February 2013

HPV in Cervical Cytology––Booth et al 219