Original Articles. Do Infection Patterns of Human Papillomavirus Affect the Cytologic Detection of High-Grade Cervical Lesions on Papanicolaou Tests?

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1 Original Articles Do Infection Patterns of Human Papillomavirus Affect the Cytologic Detection of High-Grade Cervical Lesions on Papanicolaou Tests? Siavash Azadmanesh Samimi, MD; Roxanne R. Mody, MD; Steven Goodman, MD; Eric Luna, BS; Donna Armylagos, BS; Mary R. Schwartz, MD; Dina R. Mody, MD; Yimin Ge, MD Context. Persistent infection with high-risk human papillomavirus (hrhpv) is the major cause of cervical cancer. The effect of HPV infection patterns on cytologic detection of cervical lesions is unknown. Objective. To determine the effect of HPV infection patterns on the sensitivity of cytologic detection of highgrade cervical lesions. Design. Papanicolaou tests from 257 women with biopsy-confirmed, high-grade squamous intraepithelial lesions were analyzed with respect to HPV infection patterns. Results. Among 257 biopsy-confirmed, high-grade squamous intraepithelial lesion cases, the preceding cytology showed 20 cases (8%) were benign; 166 cases (65%) were low-grade cervical lesions, including atypical squamous cell of undetermined significance and lowgrade squamous intraepithelial lesions; and 71 cases (28%) were high-grade cervical lesions, including atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (atypical squamous cell high), atypical glandular cells, and high-grade squamous intraepithelial lesions. In 236 cases tested for HPV, those exhibiting low-grade cervical lesions on cytology were often associated with coinfections of mixed hrhpv genotypes (31 of 40; 78%) or non-16/18 hrhpv (75/103; 73%), compared with single-genotype infections of HPV-16 (33 of 62; 53%) or HPV-18 (2 of 6; 33%) (P ¼.001). In contrast, highgrade cervical lesion cytomorphology tended to associate with the single-genotype infection of HPV-16 (20 of 62; 32%) or HPV-18 (3 of 6; 50%), compared with non-16/18 hrhpv (25 of 103; 24%) or multigenotype infection (8 of 40; 20%) (P ¼.01). Conclusions. Our findings suggest that multigenotypic or non-16/18 hrhpv infections often produce deceptive lower-grade cytomorphology, which could result in underdiagnosis and delay of treatment. The HPV infection patterns may offer unrecognized benefit beyond HPV genotyping and should be considered during clinical risk evaluation of women with lower-grade cytology. (Arch Pathol Lab Med. 2018;142: ; doi: / arpa oa) More than 40 genotypes of human papillomavirus (HPV) are known to infect the anogenital region. The genital HPV types are categorized according to their oncogenic potential. 1 The HPV genotypes 16 (HPV-16) and 18 (HPV- 18) potentiate approximately 70% of cervical cancer cases. 2 Accepted for publication May 24, Published as an Early Online Release November 21, From the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Drs Azadmanesh Samimi, D. Mody, Goodman, Schwartz, and Ge; Mr Luna; and Ms Armylagos); the School of Medicine, University of Texas Health Science Center, Houston (Dr R. Mody); the BioReference Laboratories, Houston (Mr Luna and Ms Armylagos); and the Department of Pathology and Genomic Medicine, Weill Medical College of Cornell University, New York, New York (Dr Ge). The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the annual meeting of the United States and Canadian Academy of Pathology; March 16, 2016; Seattle, Washington. Reprints: Yimin Ge, MD, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin St, Suite M227, Houston, TX ( yge@houstonmethodist.org). Persistent infection with oncogenic high-risk HPV (hrhpv) genotypes is the major cause of cervical cancers and precancerous lesions. 3 Studies have demonstrated that more than 85% of women with cervical cancer precursors had detectable hrhpv DNA. 4,5 In one study, the risk of developing high-grade squamous intraepithelial lesions (HSILs) was 17% and 14% for women infected with HPV- 16 and HPV-18 genotypes, respectively. In comparison, the incidence was 3% among women with positive results for other types of hrhpv. 5 The most recent consensus guidelines for screening cervical cancer recommend that women older than 30 years undergo Papanicolaou (Pap) and hrhpv testing (cotesting) every 5 years (preferred) or Pap testing only every 3 years (accepted). 6 In a previous study, the sensitivity of a single Pap test was between 60% and 80%, and the false-negative rate of 3 consecutively negative Pap test results was approximately 6%. 7 For women older than 30 years, cotesting lowered the rate of false-negative results. 8,9 The management strategy for a small group of women who have positive hrhpv and negative Pap test results is under debate. The most recent American Society of Colposcopy and Cervical Pathology management guidelines (2012) 10 Arch Pathol Lab Med Vol 142, March 2018 HPV Infections and High-Grade Lesions Samimi et al 347

2 Figure 1. Cytology diagnoses of preceding Papanicolaou tests in women with high-grade squamous intraepithelial lesions (HSILs) on follow-up biopsy: negative results for intraepithelial lesions or malignancy (NILM; 20 of 257; 8%), atypical squamous cell of undetermined significance (ASC-US; 71 of 257; 28%), atypical squamous cell, cannot rule out HSILs (ASC-H; 31 of 257; 12%), low-grade squamous intraepithelial lesion (LSIL; 95 of 257; 37%), HSIL (34 of 257; 13%), and atypical glandular cells (AGC; 6 of 257; 2%). suggested an earlier colposcopic examination for the small population of women with negative Pap test and positive HPV-16 or HPV-18 results. The effect of HPV genotype-specific infection patterns on the rate of cytologic detection of significant cervical lesions is unclear. Recent data suggest that coinfection with multiple strands of HPV potentially alters their oncogenic effect in comparison to single-genotype infection. 11 Infection with multiple genotypes of HPV reportedly occurs in 5% to 30% of infected women. 12 The current study aimed to determine the association between the genotype-specific patterns of HPV infection and the sensitivity of the Pap test in women with biopsy-confirmed HSIL. DESIGN The Pap tests recorded in our laboratory information system between March 2013 and June 2014 were analyzed along with results from hrhpv testing (Cobas 4800 system, Roche Molecular Diagnostics, Pleasanton, California) and follow-up biopsies, when available. The cervical lesions detected on Pap tests were categorized into 2 general groups: low-grade cervical lesions, encompassing atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSILs), and high-grade cervical lesions (HGCLs), including ASC, cannot rule out HSILs; atypical glandular cells; HSILs, and carcinomas. The results of follow-up biopsies, performed within 14 months of cytology-hpv cotesting, were recorded. Cervical intraepithelial neoplasia grade 2 or worse on biopsy were considered HSILs. All cervical intraepithelial neoplasia grade 2 lesions were confirmed by immunohistochemical staining for p16 and Ki-67. Real-time histologic-cytologic correlation was performed at the time of biopsy sign-out, as per our usual clinical practice. All Pap tests were performed with 1 of the 2 liquid-based methods, in accordance with the preference of the referring practitioner: ThinPrep (Hologic, Madison, Wisconsin) and SurePath (Becton Dickinson, Franklin Lakes, New Jersey). Of the 257 cases with biopsy-confirmed HSIL, the preceding Pap tests were performed on the ThinPrep platform in 133 cases (51.8%) and on the SurePath platform in 124 cases (48.2%). The indication for cervical biopsy was not solely based on the preceding Pap test results. Some patients were referred to colposcopy based on their HPV genotyping results or other clinical situations. The cytologic data acquired by our laboratory were benchmarked with the College of American Pathologists Laboratory Accreditation Program database. The Pap tests and biopsies were interpreted by board-certified cytopathologists or gynecologic pathologists in an academic medical center. RESULTS In this general screening population, the HSIL reporting rate on cytology was 0.24% (313 of cases), and there was consistent cytohistologic correlation in 70% (167 of 239) of the cases. Most cases with uncorrelated data were due to tissue-sampling variances (98%; 234 of 239 cases). A total of 257 women had HSIL on follow-up biopsies, with an average age of 37.9 years (range, years). Of the women with biopsy-confirmed HSIL, the preceding Pap test diagnoses included 20 negative results (8%) for intraepithelial lesions or malignancy; 71 cases (28%) of ASC-US; 31 (12%) ASCs, cannot rule out HSILs; 6 (2%) atypical glandular cells; 95 (37%) LSIL; and 34 (13%) HSILs (Figure 1). No carcinomas or other malignancies were identified in the group. Seventy-one cases (28%) had high-grade cytologic lesion (HGCL) index Pap test results, including ASC, cannot rule out HSILs; atypical glandular cells; and HSILs. Cobas HPV cotesting was performed in 236 of the 257 biopsy-confirmed HSIL cases (92%). Of those, hrhpv was detected in 92% (n ¼ 215) of the cases, and results were negative in 9% (n ¼ 21) of the women. The biopsies that tested positive for hrhpv showed 4 unique infection patterns: (1) single-genotype HPV-16 (62 of 215; 29%) or (2) HPV 18 (6 of 215; 3%) infections, (3) non-16/18 hrhpv infections (107 of 215; 50%), and (4) mixed infection patterns with combined HPV-16, HPV-18, and/or non-16/ 18 hrhpv (40 of 215; 19%) genotypes (Figure 2). The Pap test results with the corresponding hrhpv genotypes detected on cotesting are provided in the Table. Cytologically, low-grade cervical lesions were often associated with 2 HPV infection patterns: (1) mixed genotype (31 of 40; 77%) and non-16/18 hrhpv infection (75 of 103; 73%). However, the lower-grade cytomorphology was significantly less common in single-hpv genotype infections of HPV-16 (33 of 62; 53%) or HPV-18 (2 of 6, 33%) (P ¼.01). In contrast, HGCLs on Pap test were more often associated with single-genotype infection of HPV-18 (3 of 6; 50%) or HPV-16 (20 of 62; 32%), compared with non-16/18 hrhpv genotypes (25 of 103; 24%) or mixed infection pattern (8 of 40; 20%) (P ¼.01) (Figure 3). Among 21 women with HSIL on biopsy who tested negative for hrhpv, 19 (90%) had abnormal Pap tests, including 12 cases (57%) of HGCL and 7 cases (33%) of low-grade cervical 348 Arch Pathol Lab Med Vol 142, March 2018 HPV Infections and High-Grade Lesions Samimi et al

3 Figure 2. Infection pattern of high-risk human papilloma virus (hrhpv) in women with high-grade squamous intraepithelial lesions (HSIL) on follow-up biopsy: negative for hrhpv (21 of 215; 9% [not shown]), single-genotype HPV-16 (62 of 215; 29%), HPV-18 (6 of 215; 3%), non-16/18 hrhpv (107 of 215; 50%), and mixed pattern with combined HPV-16/18 and/or non-16/18 hrhpv (40 of 215; 19%). Percents shown in the figure exceed 100% due to rounding. lesion. Only 2 women (10%) with biopsy-confirmed HSIL had double-negative results on the preceding HPV-cytology cotesting (Table). DISCUSSION Persistent infection with hrhpv causes most cervical cancers and precancerous lesions. 3 In recent years, the Cobas hrhpv test with HPV-16/18 genotyping has been increasingly used in clinical practice as an additional test, along with the Pap test, for cervical cancer screening and triaging patients with ASC-US. The effect of HPV infection patterns on cytomorphology and detection of HGCL by the Pap test is unknown. In this study, we analyzed the association of hrhpv infection patterns with cytologic diagnoses in women with biopsy-proven HSIL. In this cohort of biopsy-confirmed HSIL, the patients were stratified into 5 groups according to the HPV test results: (1) HPV-16, (2) HPV-18, (3) non-16/18 hrhpv, (4) mixed hrhpv, and (5) negative for hrhpv. We found that the lower-grade cytomorphology (ASC-US and LSIL) was significantly associated with HPV infections of non-16/18 hrhpv and mixed hrhpv infection patterns. In contrast, single-genotype infections of HPV-16 or HPV-18 were more frequently associated with high-grade cytomorphology on Pap tests (Figure 4, A through D). Our findings suggest that non-16/18 or mixed hrhpv infections tend to produce predominantly lower-grade cytomorphology than singlegenotypic infections of HPV-16 or HPV-18 do, which may result in underdiagnosis of Pap test results and delay of clinical follow-up or necessary intervention. According to the ATHENA trial (A Trial With Dronedarone to Prevent Hospitalization or Death in Patients with Fibrillation), 12.5% of women older than 21 years had an hrhpv infection other than the HPV-16/18 genotypes. 13 In our cohort of women with biopsy-confirmed HSIL, 45% were infected with non-16/18 hrhpv and 17% with mixedhrhpv genotypes. Given that these women were more likely to have lower-grade lesions on their Pap tests, cotesting with HPV testing and genotyping likely helped reduce underdiagnosis and delay of treatment. In our previous study on women diagnosed with LSIL on cytology, those with infection of a non-16/18 hrhpv genotype were more likely to have persistent disease or to progress to HGCL. 14 This suggests that these women with LSIL cytology and non-16/18 HPV infection tended to harbor high-grade lesions and were more likely to be underdiagnosed because of deceptive lower-grade cytomorphology. According to the American Society for Colposcopy and Cervical Pathology 2012 guidelines, 10 a second colposcopic examination can be delayed by 1 to 3 years after a diagnosis of LSIL or ASC-US from Pap tests with negative HPV-16/18 results. In view of our data, a reduced threshold for colposcopy or other intervention may be considered for women infected with non-16/18 hrhpv or mixed-hrhpv genotypes. Women infected with these genotypes may harbor HGCL despite deceptive lower-grade cytomorphology. Because HPV vaccination is gradually taking effect in the North American population, the predominant HPV infection patterns are expected to change. The HPV-16 and HPV-18 genotypes may be less likely to occur over time as the predominant single-genotype infectious pattern, whereas non-16/18 hrhpv and possibly other uncommon genotypes become more prominent. 1 In addition, the significant increase in human migration around the world in recent decades has caused a dramatic change in genotypic composition of HPV in North American populations. 2,15 The shifting of HPV genotypic prevalence will have significant effect on current screening practices because infections of non-16/18 hrhpv and mixed-hpv genotypes often produce Association of Human Papillomavirus (HPV) Infection Patterns and Cytology Diagnoses in Women With Biopsy-Confirmed, High-Grade Squamous Intraepithelial Lesions hrhpv Test NILM, No. (%) LGCL, No. (%) HGCL, No. (%) Total (N ¼ 215), No. HPV-16 9 (14) 33 (53) 20 (32) 62 HPV-18 1 (16) 2 (33) 3 (50) 6 Non-16/18 hrhpv 7 (6) 75 (70) 25 (23) 107 Mixed hrhpv 1 (2) 31 (77) 8 (20) 40 Abbreviations: HGCL, high-grade cervical lesions, encompassing atypical squamous cell, cannot rule out high-grade squamous intraepithelial lesion, atypical glandular cells, and high-grade squamous intraepithelial lesion; hr, high-risk; LGCL, lower-grade cervical lesions, encompassing lowgrade squamous intraepithelial lesion and atypical squamous cells of undetermined significance; NILM, negative for intraepithelial lesions or malignancies. Arch Pathol Lab Med Vol 142, March 2018 HPV Infections and High-Grade Lesions Samimi et al 349

4 Figure 3. Association of human papilloma virus (HPV) infection patterns with cytologic detection of low-grade cytologic lesion (LGCL) and high-grade cytologic lesions (HGCL) in women with biopsy-confirmed, high-grade squamous intraepithelial lesions. Infections with mixed HPV and non-16/18 high-risk (hr)hpv genotypes often produced lower-grade cytomorphology compared with single-genotype HPV infection of HPV-16 or HPV-18, which often caused high-grade cytologic changes. deceptive lower-grade cytomorphology. Further studies are needed to establish sensitive and effective screening approaches to adapt to the growing challenge of genotypic shifting of HPV in North American populations. The mechanisms of deceptively lower-grade cytomorphology observed in women infected with non-16/18 hrhpv and mixed-hrhpv genotypes are unknown. In previous studies, multigenotype HPV infections were documented in 20% to 30% of women with HGCLs In our study cohort, at least 17% of the patients with biopsyproven HSIL demonstrated coinfection with 2 or more HPV genotypes. The actual percentage of multigenotype HPV infections in this cohort could be much higher because 45% of the women were infected with non-16/18 hrhpv, which could represent single or multiple genotypes in a battery of the remaining 12 hrhpv types. A host of different immunomodulatory mechanisms has been suggested for the lower-grade lesions in multigenotype HPV infections. 19 Recent studies suggest viral antagonistic interaction among a number of HPV genotypes. 20 This result was based on observations that patients who are seropositive for multiple HPV types have a lower risk of developing cervical cancer. 21 The mechanism of intergenotypic competition is complex and depends on all stages of infection, from binding sites/ receptors to genomic expression within host cells and interaction with the immune system of the host. Further studies are needed to unravel the underlying mechanism. The Cobas platform detects 14 hrhpv genotypes, including HPV-16 and HPV-18, in addition to HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68, commonly referred to as non-16/18 hrhpv types. 22 The sensitivity and specificity of the Cobas HPV for detecting hrhpvs were 91.7% and 97.0%, respectively. 23 A previous study 9 showed 21 of 236 biopsy-proven HSIL cases (9%) with no detectable HPV on the Cobas platform. This could be due to infection with rare HPV genotypes, which are not covered by the testing panel of the Cobas platform. Other potential contributing factors include sampling variation, low viral loads, technical errors, truly non-hpv driven lesions, as well as false-negative results because of interference from reagents. 9 This finding raises a question about the effectiveness of the Cobas HPV testing as a primary-screening method for high-grade cervicovaginal lesions. Our data clearly demonstrated that the false-negative rate was greatly reduced by combining cytology and HPV testing, thus providing further support for cytology-hpv cotesting as the best current strategy for detection of high-grade cervicovaginal lesions. Despite the observed trends in this study, our results should be interpreted cautiously because most of the biopsies were performed within 1 year of the Pap tests, which is shorter than the 3-year window recommended by the US Preventive Services Task Force. This limits the ability to observe the effects of delayed diagnosis because of the false-negatives on screening and the corresponding followup results. In this small cohort, the HSIL correlation rate between cytology and biopsy was misleadingly low because the study group did not include women with Pap test results alone or those with HSIL on a Pap test but who had the biopsy performed elsewhere. On the other hand, some women were referred to colposcopy because of positive HPV test results, regardless of their Pap test results, which may also be a contributing factor. In addition, this is a retrospective, cross-sectional study, and follow-up data regarding the long-term effect of cytologic changes in patients with single versus multiple genotype infections of HPV are not available for assessment. The focus of this study was to investigate the association of cytomorphologic changes with the pattern of HPV genotype infection, regardless of immunomodulatory factors, such as tobacco use, HIV status, sexual history, and prior history of cervical intraepithelial lesions. Our study had a relatively small cohort of biopsy-proven HSIL cases, a fact which limited our interpretation of the less-frequent HPV genotypes. Given the limited genotyping panel of the Cobas 4800, we were unable to further analyze the interaction among various HPV genotypes, in the group with multigenotype HPV infection. 350 Arch Pathol Lab Med Vol 142, March 2018 HPV Infections and High-Grade Lesions Samimi et al

5 Figure 4. Representative photomicrographs of Papanicolaou tests in women with various human papilloma virus (HPV) infection patterns. In this biopsy-confirmed, high-grade squamous intraepithelial lesions cohort lower-grade cytomorphology was often seen in mixed HPV-16/18 (A) and non- 16/18 hrhpv (B) infections, whereas high-grade cytologic features were more frequently associated with single-genotype infection with HPV-16 (C) or HPV-18 (D) (Papanicolaou, original magnification 3400 [A through D]). In the cohort with biopsy-confirmed HSILs, the women infected with non-16/18 hrhpv or mixed-hpv genotypes were significantly associated with deceptive lower-grade cytomorphology, compared with those infected with single HPV-16 or HPV-18 genotypes, contributing to falsenegative results or underdiagnosis on Pap tests. Clinically, HPV testing provides valuable information on HPV infection patterns, which may help in risk stratification. Vigilant surveillance and dynamic management protocols may be warranted for women infected with non-16/18 hrhpv or mixed-hpv genotypes. Information provided by HPV testing and genotyping likely is far greater than solely HPV-16/18. The overall infection pattern can be increasingly valuable in clinical risk management in light of the current challenges of HPV genotype shifting because of vaccination and human migration. Further studies of the mechanisms and the interactions among various HPV genotypes are needed to establish appropriate guidelines regarding followup and management of these patients. We thank Helen Chifotides, PhD, for editing of the manuscript. References 1. Gerberding, JL; Department of Health and Human Resources, eds. Centers for Disease Control(CDC): Prevention of Genital Human Papillomavirus Infection. Published January Accessed June Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88(1): Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med. 2005;353(20): Herrero R, Hildesheim A, Bratti C, et al. Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst. 2000;92(6): Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97(14): Saslow D, Solomon D, Lawson HW, et al; American Cancer Society; American Society for Colposcopy and Cervical Pathology; American Society for Clinical Pathology. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012;137(4): Coppleson LW, Brown B. Estimation of the screening error rate from the observed detection rates in repeated cervical cytology. Am J Obstet Gynecol. 1974;119(2): Moyer VA; US Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement [published correction appears in Ann Intern Med. 2013;158(11):852]. Ann Intern Med. 2012;156(12): Arch Pathol Lab Med Vol 142, March 2018 HPV Infections and High-Grade Lesions Samimi et al 351

6 9. Zhou H, Mody RR, Luna E, et al. Clinical performance of the Food and Drug Administration Approved high-risk HPV test for the detection of high-grade cervicovaginal lesions. Cancer Cytopathol. 2016;124(5): American Society for Colposcopy and Cervical Pathology. Algorithms: Updated Consensus Guidelines for Managing Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Published August Accessed July Salazar KL, Zhou HS, Xu J, et al. Multiple human papilloma virus infections and their impact on the development of high-risk cervical lesions. Acta Cytol. 2015;59(5): Bauer HM, Ting Y, Greer CE, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA. 1991;265(4): Wright TC Jr., Stoler MH, Behrens CM, Sharma A, Sharma K, Apple R. Interlaboratory variation in the performance of liquid-based cytology: insights from the ATHENA trial. Int J Cancer. 2014;134(8): Lyons Y, Kamat A, Zhou H, et al. Non-16/18 high-risk HPV infection predicts disease persistence and progression in women with an initial interpretation of LSIL. Cancer Cytopathol. 2015;123(7): Zhou H, Mody D, Schwartz M, et al. Genotype-specific prevalence and distribution of human papillomavirus genotypes in underserved Latino women with abnormal Papanicolaou tests. J Am Soc Cytopathol. 2014;3(1): Chaturvedi AK, Katki HA, Hildesheim A, et al; CVT Group. Human papillomavirus infection with multiple types: pattern of coinfection and risk of cervical disease. J Infect Dis. 2011;203(7): Franco EL, Villa LL, Sobrinho JP, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis. 1999;180(5): Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM; ALTS Group. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis. 2007;195(11): Silins I, Wang Z, Avall-Lundqvist E, et al. Serological evidence for protection by human papillomavirus (HPV) type 6 infection against HPV type 16 cervical carcinogenesis. J Gen Virol. 1999;80(pt 11): Sobota RS, Ramogola-Masire D, Williams SM, Zetola NM. Co-infection with HPV types from the same species provides natural cross-protection from progression to cervical cancer. Infect Agent Cancer. 2014;9:26. doi: / Luostarinen T, af Geijersstam V, Bjrge T, et al. No excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11. Int J Cancer. 1999;80(6): Heideman DA, Hesselink AT, Berkhof J, et al. Clinical validation of the Cobas 4800 HPV test for cervical screening purposes. J Clin Microbiol. 2011; 49(11): Park Y, Lee E, Choi J, Jeong S, Kim HS. Comparison of the Abbott RealTime high-risk human papillomavirus (HPV), Roche Cobas HPV, and Hybrid Capture 2 assays to direct sequencing and genotyping of HPV DNA. J Clin Microbiol. 2012; 50(7): Submissions Now Accepted for the CAP18 Abstract Program Abstract and case study submissions to the College of American Pathologists (CAP) 2018 Abstract Program are now being accepted. Pathologists, laboratory professionals, and researchers in related fields are encouraged to submit original studies for possible poster presentation at the CAP18 meeting. Submissions will be accepted until 5 p.m. Central Friday, March 9, Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only supplement to the September 2018 issue. The CAP18 meeting will be held from October 20 to 24 in Chicago, Ill. Visit the CAP18 Web site ( and the Archives Web site (www. archivesofpathology.org) for additional abstract program information as it becomes available. 352 Arch Pathol Lab Med Vol 142, March 2018 HPV Infections and High-Grade Lesions Samimi et al