Detecting High-Grade Cervical Disease on ASC-H Cytology. Role of BD ProEx C and Digene Hybrid Capture II HPV DNA Testing

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1 Anatomic Pathology / BD ProEx C Use in ASC-H Cy t o l o g y Detecting High-Grade Cervical Disease on ASC-H Cytology Role of BD ProEx C and Digene Hybrid Capture II HPV DNA Testing Momin T. Siddiqui, MD, FIAC, 1 Cynthia Cohen, MD, 1 and Aziza Nassar, MD, FIAC 2 Key Words: Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion; ASC-H cytology; BD ProEx C; High-risk human papillomavirus DNA test DOI: /AJCPWW6V2KGXODUI Abstract The BD ProEx C stain (BD Diagnostics-Tripath, Burlington, NC) detects 2 molecular markers known to be overexpressed in cervical squamous cell carcinoma, minichromosome maintenance protein 2 and topoisomerase II. This study was conducted to evaluate this stain detecting high-grade cervical disease, and results were compared with high-risk HPV (hr-hpv) status and histologic biopsy diagnosis in Papanicolaou tests with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) cytologic results. Cervical cytology specimens were collected in BD SurePath preservative (BD Diagnostics-Tripath), and 100 specimens with a diagnosis of ASC-H were included in the study. A second BD SurePath slide, prepared from the residual cellular material from these ASC-H cases, was immunostained using the BD ProEx C reagent. Nuclear staining of ASC-H cells was considered a positive result. The sensitivity for BD ProEx C for detecting cervical intraepithelial neoplasia 2 or worse was 98.8% and for hr-hpv was 71.1%, whereas specificity values were 82.4% and 64.7%, respectively. BD ProEx C has potential as a marker for detection of high-grade disease in patients with ASC-H cytologic results. The Papanicolaou (Pap) test can be credited for decreasing the morbidity and mortality associated with cervical carcinoma, universally. 1 However, cervical carcinoma still remains the second most common malignancy in women worldwide and is the most common female malignancy in developing third-world countries. 2 Approximately 50% of patients with cervical carcinoma have never been screened. 3-5 In addition, approximately 30% of patients with cervical cancer also have had at least 1 false-negative Pap test result because of errors in sampling or cytologic interpretation, before the development of invasive cervical carcinoma. 6 Hence, any single Pap test event is only 50% sensitive for detecting the presence of disease. 7 The Atypical Squamous Cells of Undetermined Significance (ASC-US) Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study (ALTS) also found that 12% of women with ASC-US cytologic results had an underlying high-grade squamous intraepithelial lesion (HSIL). 8,9 This finding indicates that an estimated 3 million American women receiving abnormal Pap test results would require colposcopy to exclude HSIL. 10 These limitations encountered with the Pap test are now being addressed by ancillary molecular testing of cervicovaginal samples. High-risk human papillomavirus (hr-hpv) DNA testing is one of these ancillary tests that can separate women with an ASC-US diagnosis into a negative or a positive group, with each group having a different risk for HSIL. A negative hr-hpv DNA result carries a very low risk of HSIL and is similar to the risk for a woman who has a diagnosis of negative for intraepithelial lesion (NILM). 11 Hence, women with a diagnosis of NILM on the Pap test and a negative HPV DNA test may have a very low risk of HSIL, and the screening interval for them may be increased Am J Clin Pathol 2008;130: DOI: /AJCPWW6V2KGXODUI 765

2 Siddiqui et al / BD ProEx C Use in ASC-H Cy t o l o g y Data for the positive group, represented by a positive HPV DNA test, however, show very low specificity for HSIL. 15 In view of this, the most helpful molecular marker for detecting HSIL should have the negative predictive value (NPV) of a negative HPV DNA test and a higher positive predictive value (PPV). The BD ProEx C (BD Diagnostics-Tripath, Burlington, NC) may be a helpful marker in this regard. It is an immunocytochemical assay that identifies the expression of topoisomerase II-α (TOP2A) and minichromosome maintenance protein-2 (MCM2). 16,17 TOP2A and MCM2 have been identified by transcriptional profiling as genes that are overexpressed in cervical carcinoma Their overexpression results from the malfunction of 2 critical cell cycle checkpoints resulting from persistent HPV infection. Two HPV oncoproteins are directly involved in the development of cervical dysplasia and carcinoma. The E6 oncogene interacts with the p53 tumor suppressor protein, abrogating cell cycle checkpoints at the G 1 /S and G 2 /M boundaries. The E7 oncogene, through interaction with hypophosphorylated RB proteins prb, p107, and p130, promotes acceleration into S-phase, with prolonged expression of the S-phase genes required for DNA replication such as TOP2A and MCM2, resulting in aberrant S-phase induction. 21 In DNA synthesis and proliferation, TOP2A causes enzymatic unlinking of DNA strands during replication, and MCM2 functions during DNA replication by loading the prereplication complex into DNA via the unwinding of DNA through helicase activity, thus permitting DNA synthesis. 22 The present study was undertaken to compare the ability of BD ProEx C immunocytochemical staining and highrisk Digene Hybrid Capture II HPV DNA test (Digene, Gaithersburg, MD) to detect high-grade cervical disease and was performed on liquid-based BD SurePath cytologic specimens (BD Diagnostics-Tripath) with a diagnosis of atypical squamous cells, cannot exclude HSIL (ASC-H). Materials and Methods The study protocol was approved by the institutional review board, Emory University Hospital, Atlanta, GA. A total of 100 specimens were collected for this study. These specimens were residual cervicovaginal cytology samples collected in BD SurePath preservative that were obtained from the Emory Cytopathology Laboratory from 2005 until 2007, after clinical evaluation was completed and a diagnosis of ASC-H was made. The BD SurePath residual pellet was retrieved within 48 hours for processing of an additional unstained slide for BD ProEx C immunocytochemical studies and hr-hpv testing. Histologic biopsy diagnoses for all cases were also available for review. BD SurePath processed, unstained slides were stained with BD ProEx C, which is a class I, in vitro, immunocytochemical stain that is used with standard immunocytochemical techniques to detect aberrant S-phase induction. The BD ProEx C stain contains antibodies to TOP2A and MCM2 proteins. The BD SurePath processed slides were prepared by using the BD PrepStain processor (BD Diagnostics-Tripath) and were treated with a pretreatment buffer for target retrieval using the BD SureDetect slide-preparation buffer (BD Diagnostics- Tripath). Immunocytochemical staining was performed with BD ProEx C using a detection reagent kit that includes prediluted antibody, a 3,39-diaminobenzidine tetrahydrochloride based chromogen, and hematoxylin-based counterstains (BD SureDetect detection reagents and BD SureDetect counterstains), on an automated staining platform (DAKO Autostainer; DakoCytomation, Carpinteria, CA). The slides were coverslipped, and the entire surface area of each specimen was reviewed to confirm the absence of nonspecific staining and to confirm nuclear staining of the BD ProEx C stain. A positive control slide with SiHa cells was included in each run and was reviewed to confirm adequate staining. The slides were then scored by using conventional microscopy. The slides were interpreted for BD ProEx C staining and scored using a 3-step algorithm. The first step was to determine the adequacy of the specimen according to the 2001 Bethesda System criteria. 23 The second step was determining if there was brown nuclear staining in squamous cells. The third step was to determine if the BD ProEx C stained cells were abnormal and conforming to the diagnostic criteria of ASC-H. If all 3 criteria were met, the slide was interpreted as positive. In the presence of an adequate number of cells, the absence of BD ProEx C staining or staining only in cytologically normal cells resulted in a negative interpretation. The Digene Hybrid Capture II HPV DNA test was performed on all BD SurePath specimens at ARUP Laboratories (Salt Lake City, UT) according to the manufacturer s instructions. The samples were received within 1 day of collection and stored at room temperature until testing was performed within 2 weeks of specimen collection. Digene Hybrid Capture II HPV DNA testing was performed according to the manufacturer s recommendations using the high-risk probes with the positive and negative control samples run in triplicate and result validation using HC2 software, version 2.0. The hr-hpv panel consisted of 13 types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). The hybridized product is detected by a chemiluminescent reporter system. The test results are given as relative light unit ratios. The manufacturer has set a positive cutoff value of 1 pg/ml of HPV DNA in the specimen. 766 Am J Clin Pathol 2008;130: DOI: /AJCPWW6V2KGXODUI

3 Anatomic Pathology / Original Article Results In this study, samples from a total of 100 patients with an ASC-H diagnosis were studied. Their ages ranged from 21 to 79 years. ztable 1z includes the BD ProEx C and hr- HPV results along with biopsy data. BD ProEx C staining was detected in 85 of 100 ASC-H cases zimage 1z, zimage 2z, and zimage 3z. Sporadic staining of endocervical cells was also identified in 79 cases; however, morphologically, these cells were not atypical and, hence, were not scored as positive zimage 4z. Cervical biopsy data were used as the gold standard for calculation of the sensitivity, specificity, PPV, and NPV for the detection of high-grade disease ztable 2z. The sensitivity for detecting high-grade (cervical intraepithelial neoplasia [CIN] 2+) disease by BD ProEx C and hr-hpv were 98.8% and 71.1%, respectively, whereas the specificity for detecting high-grade disease for BD ProEx C and hr-hpv were 82.4% and 64.7%, respectively. In addition, the sensitivity, specificity, PPV, and NPV for detecting CIN 1+ disease were also determined ztable 3z. Discussion An estimated 11,150 American women were diagnosed with cervical carcinoma in In addition, there are data indicating that more than 3 million women annually receive an equivocal Pap test result. 25 These women may then undergo HPV testing, colposcopy, or a cervical biopsy to exclude the presence of high-grade dysplasia or squamous cell carcinoma. With this background, the present study was conducted in cases with an ASC-H diagnosis to determine if use of the BD ProEx C immunocytochemical test could serve as an improved, noninvasive test to better identify women at a high risk of having high-grade cervical disease. The Digene Hybrid Capture II HPV DNA test is a molecular test that detects HPV and is used in patients with ASC- US, ASC-H, and LSIL diagnoses to identify patients with hr-hpv. 26 This test, however, has limitations owing to limited specificity. A recent meta-analysis reported that the sensitivity and specificity for HPV DNA testing using the Digene Hybrid Capture II HPV DNA test for detecting high-grade cervical disease were 94.8% and 67.3%, respectively. 27 Another study reported a false-positive rate of 6.2% for HPV DNA testing when used in the setting of cervical cancer screening rather than for triaging patients with an ASC-US diagnosis. 28 In addition, the false-negative rate for the Digene Hybrid Capture II HPV DNA test ranges from 3.7% to 18.2%. 28,29 In view of these findings, additional new tests need to be developed, and their usefulness in detecting high-grade cervical disease needs to be studied. Kelly et al 16 validated BD ProEx C in a retrospective analysis and determined its PPV in biopsy-proven cases of HSIL. The PPV for BD ProEx C was 44.6% in patients with an ASC-US diagnosis. This study also showed that 100% of the HSIL cytology samples were positive with BD ProEx C. In addition, this study found that 25% of the LSIL cytologic samples were positive for BD ProEx C, with 30% of samples that were concordant on LSIL cytology and CIN 1 biopsy positive for BD ProEx C. This finding raises the possibility that this marker may be detecting high-grade disease in patients with LSIL cytologic results and needs to be further studied in detail. Our present study showed 7 biopsy-proven CIN 1 cases with only 1 case with BD ProEx C positivity. The usefulness of BD ProEx C in cervical cytology was also determined in another recent study. Shroyer et al 30 examined BD ProEx C staining in normal and SiHa-spiked cells and HSIL cases. SiHa cells are a control cell line derived from a patient with American Joint Committee on Cancer grade 2 squamous cell carcinoma of the cervix and reported to contain 1 to 2 copies of the integrated HPV-16 genome per cell. BD ProEx C demonstrated 100% sensitivity and specificity for the classification of slides that were positive or negative for SiHa or HSIL cells. The second component of the study by Shroyer et al 30 evaluated 40 clinical samples, which included 10 cases each with a diagnosis of NILM, ASC-US, LSIL, and HSIL. It was noted that BD ProEx C staining was uniformly absent in all cases with a diagnosis of NILM and uniformly positive in all cases with a diagnosis of ztable 1z Follow-up Biopsy, BD ProEx C, and Digene Hybrid Capture II HPV DNA Test Results for 100 Study Cases of Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion * Positive Results Diagnostic Category Cervical Biopsy Results BD ProEx C Digene Hybrid Capture II HPV DNA Test Negative for dysplasia CIN CIN CIN CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. * Data are given as number of cases. Am J Clin Pathol 2008;130: DOI: /AJCPWW6V2KGXODUI 767

4 Siddiqui et al / BD ProEx C Use in ASC-H Cy t o l o g y zimage 1z A single atypical cell with morphologic features consistent with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, showing dark nuclear staining with the BD ProEx C (immunocytochemical stain, 400). zimage 2z The nuclear contours of these BD ProEx C stained atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, are irregular (immunocytochemical stain, 600). zimage 3z A hyperchromatic crowded group of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, with positive nuclear staining with the BD ProEx C (immunocytochemical stain, 600). zimage 4z A group of reactive endocervical cells with rare cells staining with the BD ProEx C (immunocytochemical stain, 600). HSIL. ASC-US and LSIL cases showed BD ProEx C positivity in 20% and 50% of the cases, respectively. Our study effectively studied 100 cases with an ASC-H diagnosis with subsequent BD ProEx C and hr-hpv testing and biopsy diagnosis review. Of the cases, 83.0% had high-grade (CIN 2+) disease. BD ProEx C showed a statistically significant increase in the sensitivity for the detection of cervical disease compared with the Digene Hybrid Capture II HPV DNA test (98.8% vs 71.1%; P <.001). An increased specificity using BD ProEx C compared with the Digene Hybrid Capture II HPV DNA test was also observed (82.4% vs 64.7%) for detection of high-grade (CIN 2+) disease (Table 2), although the results did not reach statistical significance (P =.2482), likely owing to the small sample in this study. 768 Am J Clin Pathol 2008;130: DOI: /AJCPWW6V2KGXODUI

5 Anatomic Pathology / Original Article ztable 2z Performance Characteristics for BD ProEx C and Digene Hybrid Capture II HPV DNA Tests for the Detection of Cervical Intraepithelial Neoplasia 2 Disease or Worse in 100 Study Cases With Cytologic Results of Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion * Evaluated Test Sensitivity Specificity Positive Predictive Value Negative Predictive Value BD ProEx C 98.8 ( ) 82.4 ( ) 96.5 ( ) 99.3 ( ) Digene Hybrid Capture II HPV DNA 71.1 ( ) 64.7 ( ) 90.8 ( ) 31.4 ( ) HPV, human papillomavirus. * Values are given as percentages (95% confidence interval). ztable 3z Performance Characteristics for BD ProEx C and Digene Hybrid Capture II HPV DNA Tests for the Detection of Cervical Intraepithelial Neoplasia 1 Disease or Worse in 100 Study Cases With Cytologic Results of Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion * Evaluated Test Sensitivity Specificity Positive Predictive Value Negative Predictive Value BD ProEx C 92.2 ( ) 80.0 ( ) 97.6 ( ) 53.3 ( ) Digene Hybrid Capture II HPV DNA 67.8 ( ) 60.0 ( ) 93.8 ( ) 17.1 ( ) HPV, human papillomavirus. * Values are given as percentages (95% confidence interval). These data, if reviewed in the context of the earlier studies, show that BD ProEx C staining may prove to be a valuable tool in the armamentarium for diagnosing cervical disease in the future. 16,30 We found that there are 2 important features of BD ProEx C staining. First, it can, even at low microscopic magnification, identify atypical cells on the slide, which potentially aids in the identification of rare high-grade disease cells. Second, the stain has an interpreter function in which the presence of brown nuclear staining of atypical cells can correlate with a high likelihood of CIN 2+ disease. These 2 features can prove to be important to practicing cytopathologists and cytotechnologists in the realm of screening for rare atypical cells. BD ProEx C staining requires careful interpretation because, occasionally, it may be observed in reactive endocervical cells, which has been reported previously. 30 We observed this in 79 of our own cases (Image 4). This may represent a potential diagnostic pitfall, and it highlights the importance of correlating cell morphologic features with BD ProEx C staining results. We reiterate the important issue here that not all brown nuclear staining implies a positive BD ProEx C result but requires a morphologic interpretation of the stained cells as well. The exact etiology of why benign endocervical cells may show nuclear staining has not been ascertained. One possibility is that inflammation and its mediators may be responsible for this expression in benign endocervical cells. Our study shows that BD ProEx C could be used to improve the diagnostic accuracy of cervical cytology in liquidbased specimens for detecting high-grade disease, especially when it is present in rare cells. Its usefulness, especially in cases with a diagnosis of ASC-H, may help in further upgrading the diagnosis to reflect the true presence of highgrade disease. In the future, it may also serve as a useful cytologic adjunct in improving the sensitivity and specificity of the Pap test. From the Departments of Pathology, 1 Emory University Hospital, Atlanta, GA; and 2 Mayo Clinic, Rochester, MN. Address correspondence to Dr Siddiqui: Dept of Pathology, Emory University Hospital, 1364 Clifton Rd, NE, Atlanta, GA References 1. Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer, , featuring population-based trends in cancer treatment. J Natl Cancer Inst. 2005;97: Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2000: Cancer Incidence: Mortality and Prevalence Worldwide. Version 1.0. Lyon, France: IARC Press; IARC Cancer Base No Kinney WK, Manos MM, Hurley LB, et al. Where is the high grade cervical neoplasia? the importance of minimally abnormal Papanicolaou diagnoses. Obstet Gynecol. 1998;91: Stoler MH. Cervical cancer screening in the HPV era: what is the standard of care? Presented at: Pathology Today: American Society of Clinical Pathology 2005 Annual Meeting; October 8-11, 2005; Seattle, WA. Session SP Kinney W, Sung HY, Kearney KA, et al. Missed opportunities for cervical cancer screening of HMO members developing invasive cervical cancer. Gynecol Oncol. 1998;71: Sawaya GF, Grimes DA. New technologies in cervical cytology screening: a word of caution. Obstet Gynecol. 1999;94: Am J Clin Pathol 2008;130: DOI: /AJCPWW6V2KGXODUI 769

6 Siddiqui et al / BD ProEx C Use in ASC-H Cy t o l o g y 7. Nanda K, McCrory DC, Myers ER. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytological abnormalities: a systematic review. Ann Intern Med. 2000;132: Cox JT, Schiffman M, Solomon D; for the ASCUS-LSIL Triage Study (ALTS) Group. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol. 2003;188: Sherman ME, Solomon D, Schiffman M; for the ALTS Group. Qualification of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study. Am J Clin Pathol. 2001;116: Davey DD, Woodhouse S, Stryer P, et al. Atypical epithelial cells and specimen adequacy: current laboratory practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2000;124: Solomon D, Schiffman M, Tarone R; for the ALTS Study Group. 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: Waxman AG. Guidelines for cervical cancer screening: history and scientific rationale. Clin Obstet Gynecol. 2005;48: Wang SS, Walker H, Schiffman M, et al. Evaluating the risk of cervical precancer with a combination of cytologic, virologic, and visual methods. Cancer Epidemiol Biomarkers Prev. 2005;14(11 pt 1): Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95: Schiffman M, Khan MJ, Solomon D, et al. A study of the impact of adding HPV types to cervical cancer screening and triage tests. J Natl Cancer Inst. 2005;97: Kelly D, Kincaid E, Fransier Z, et al. Detection of cervical highgrade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProEx C). Cancer. 2006;108: Malinowski DP. Molecular diagnostic assays for cervical neoplasia: emerging markers for the detection of high-grade cervical disease. Biotechniques. 2005;38(suppl): Murphy N, Ring M, Heffron CCBB, et al. p16ink4a, CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer. J Clin Pathol. 2005;58: Chen Y, Miller C, Mosher R, et al. Identification of cervical cancer biomarkers by cdna and tissue microarrays. Cancer Res. 2003;63: Santin AD, Zhan F, Bignotti E, et al. Gene expression profiles of primary HPV 16 and HPV 18 infected early stage cervical cancers and normal cervical epithelium: identification of novel candidate biomarkers for cervical cancer diagnosis and therapy. Virology. 2005;331: Freeman A, Morris LS, Mills AD, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res. 1999;5: Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70: Solomon D, Nayar R, eds. The Bethesda System for Reporting Cervical Cytology. 2nd ed. New York, NY: Springer; American Cancer Society. Cancer Facts and Figures Atlanta, GA: American Cancer Society; Schiffman M, Solomon D. Findings to date from the ASC-US-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127: Lorincz AT, Richart RM. HPV-DNA testing as an adjunct to cytology in cervical screening programs. Arch Pathol Lab Med. 2003;127: Arbyn M, Buntinkx F, Van Ranst M, et al. Virologic versus cytologic triage of women with equivocal Pap smears: a metaanalysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst. 2004;96: de Cremoux P, Coste J, Sastre-Garau X, et al. Efficiency of the Hybrid Capture 2 HPV DNA test in cervical cancer screening: a study by the French Society of Clinical Cytology. Am J Clin Pathol. 2003;120: Guo M, Hu L, Baliga M, et al. The predictive value of p16ink4a and Hybrid Capture 2 human papillomavirus testing for high-grade cervical intraepithelial neoplasia. Am J Clin Pathol. 2004;122: Shroyer KR, Homer P, Heinz D, et al. Validation of a novel immunocytochemical assay for topoisomerase II-α and minichromosome maintenance protein 2 expression in cervical cytology. Cancer. 2006;108: Am J Clin Pathol 2008;130: DOI: /AJCPWW6V2KGXODUI

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