Interpretation Guide for Ventana INFORM HPV Probes In Situ Hybridization (ISH) Staining of Cervical Tissue

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1 Interpretation Guide for Ventana INFORM HPV Probes In Situ Hybridization (ISH) Staining of Cervical Tissue Thomas M. Grogan, M.D. Hiro Nitta, Ph.D. Lidija Pestic-Dragovich, Ph.D. Lizhen Pang, M.S. Jay Ji, Ph.D. Innovations in Science and Medicine

2 Table of Contents I. Introduction A. General Description of INFORM HPV Probes B. Purpose of Interpretive Guide II. III. IV. Identification of Appropriate Staining Pattern A. Staining Patterns of Episomal and Integrated HPV B. Definition of Positive and Negative Results C. HPV Pattern and Disease Progression Representative Clinical Case Materials A. Normal B. Cervical Intraepithelial Neoplasia (CIN) I C. Cervical Intraepithelial Neoplasia (CIN) II/III D. Squamous Cell Carcinoma E. Condyloma Use of Control Slides for System Quality Control V. Alu Positive Control Probe II for Tissue Qualification VI. VII. Fixation Interpreting Artifacts A. Over-digestion Artifacts B. Leukocyte-associated Artifacts C. Drying Artifacts D. Chromogen Precipitate Artifact E. Nuclear Artifact VIII. Bibliography

3 I. Introduction A. General Description of INFORM HPV Probes The INFORM HPV III Family 16 Probe (B) contains a cocktail of HPV genomic probes in a formamide-based diluent. The intended targets are the common high-risk HPV genotypes found to be associated with cervical neoplasia. The probe cocktail has demonstrated affinity to the following genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66. The INFORM HPV II Family 6 Probe (B) contains a cocktail of HPV genomic probes in a formamide-based diluent. The intended targets are the HPV genotypes found commonly in condyloma and some early cervical intraepithelial lesions, which are not commonly associated with cervical cancer. The probe cocktail has demonstrated affinity to the following genotypes: 6 and 11. B. Purpose of Interpretive Guide The following 53 cases illustrate the variety of staining patterns that may be present in cervical biopsies when stained with Ventana INFORM HPV Probes (Figures 1-19). The photomicrographs allow a new user to become familiar with the spectrum of staining patterns including episomal and integrative patterns of HPV positivity and patterns of artifactual staining that they may encounter in a variety of cervical tissues, including normal, cervical intraepithelial neoplasia (CIN I, II / III), carcinoma, and condyloma, when using a validated assay involving the Ventana INFORM HPV Probes. The intent is to provide pathologists with a tool to facilitate interpretation of INFORM HPV Probes staining results. Any staining performed in the end users lab should be interpreted within the context of the controls run with the clinical cases at the time of evaluation. See the package insert provided with these products for further information. The images contained in this interpretive guide we obtained using an assay developed and validated at Ventana Medical Systems, Inc., employing the INFORM HPV Probes.

4 II. Identification of Appropriate Staining Pattern A. Staining Patterns of Episomal and Integrated HPV When utilizing the INFORM HPV III Family 16 Probe (B) in the Ventana-validated assay, the presence of HPV is demonstrated when either the episomal or integrated pattern is found within the nuclei of cervical epithelial cells (Figure1). (e.g. a field of epithelial cells with dot-like nuclear spots), which is pivotal to judging positivity. In contrast, the finding of a rare speck of navy-blue in a rare scattered cell could be artifactual as a pattern of cellular involvement is not evident. The episomal pattern appears as a large, homogeneous, globular navy-blue precipitate within the epithelial cell nucleus (see Cases 1-3). The integrative pattern is a discrete, stippled navy blue nuclear pattern (see Cases 4-6). As shown in Cases 1-3, the episomal pattern is generally prominent in the superficial keratinized region of the epithelium often within koilocytotic cells. The discrete, dot-like nuclear integrative pattern is more often in groups of epithelial cells in a more basal location (Case 7, Figure 2). In some cases, the nuclear integrative pattern may be so discrete as to require microscopic examination at higher magnification (40x or 100x objective) to judge nuclear epithelial cell localization. In this context, it is specifically the finding of a distinct pattern Fig. 1 Staining Patterns With INFORM HPV III Family 16 Probe (B) Episomal Pattern: Cases 1-3 These characteristic nuclear epithelial cell patterns of staining indicate positivity. In contrast, artifactual non-specific staining unrelated to HPV manifests distinctly separate features. As illustrated in Section VII, the non-specific, non-hpv associated artifacts may include focal non-cellular stromal precipitates, a slight diffuse low-level light blue staining, the periodic staining of the cytoplasm of PMNs and eosinophils, and non-specific staining of nucleoli and lymphocyte/endothelial cells. With some of these artifacts, it again may be necessary to examine borderline cases at higher magnification (40x or 100x objective) to judge nuclear localization. Case 1 Integrative Pattern: Cases 4-6 Case 2 Case 3 Case 4 Case 5 Case 6 4

5 B. Definition of Positive and Negative Results Case 7 (Figure 2) illustrates the quintessential features of judging INFORM HPV III Family 16 Probe (B) staining when using the Ventana-validated assay. The case is an example of Cervical Intraepithelial Neoplasia (CIN I) at the transition zone of the cervix. In this case, the CIN I lesional tissue (right side of photo) is seen in close contiguity with adjacent normal cervical epithelial (left side of photo). In this example, there are two positive patterns: (1) the episomal staining within the superficial epithlial cells overlying the CIN I lesional tissue and (2) the discrete, dot-like nuclear, or integrative, pattern in the mid-and basal layer CIN lesional tissue. Importantly, a negative staining pattern is found within the non-lesional adjacent normal cervical epithelial nuclei, endocervical glands, and the stromal cells, including fibroblasts, endothelial cells, and lymphocytes. Of note is a very superficial layer of navy-blue India Ink used at colposcopy to mark lesional tissue. Fig. 2 Interpretive Example: Case 7 As shown in Case 7, the determination of a true positive INFORM HPV III Family 16 Probe (B) ISH result requires finding either the episomal and/or integrative pattern of navy-blue staining in lesional cervical epithelium, in the context of adjacent negative staining within non-lesional cervical epithelium and endocervical glands and in non-lesional stromal cells, fibroblasts, lymphocytes, and endothelial cells, while discounting artifactual staining, such as found in the cytoplasm of PMN and India Ink margins. Substantial artifactual staining of non-lesional cells of epithelial or non-epithelial origin may preclude judging a positive result. The determination of a true negative INFORM HPV III Family 16 Probe (B) ISH result requires finding no signal (neither globular episomal or discrete integrative pattern) within lesional epithelial cells, in the context of a nuclear DNA-positive control probe result and an appropriate cell line slide control (Section IV and V). Normal Episomal Integrated 5

6 B. Definition of Positive and Negative Results (cont.) In some instances, particularly with high-grade dysplastic cervical lesions (eg CIN II/III or Cervical Carcinoma), the staining may show a low copy number integrative pattern, which may be most noticeable at higher microscope magnification (eg 40x or 100x objective). Figure 3 illustrates two such cases, one with a HeLa-like (10-50 copy) integrated pattern and another SiHa-like very low copy number. In both cases, the pivotal observation is the finding of a discrete, speckled nuclear localization involving numerous contiguous cervical epithelial cells with the adjacent stroma, lymphocytes, submucosal glands, and normal cervical epithelial showing an absence of this pattern. Fig. 3 Instructive Cases: Case 8 (a, b) and Case 9 (c, d) A 10X B 40X C 40X D 100X C. HPV Pattern and Disease Progression As illustrated in Figures 4A and 4B, the viral copy number and pattern of nuclear involvement varies with disease progression. Initially with CIN I and CIN II, the globular episomal pattern predominates consistent with the high viral copy number and high infectivity of the patient. Subsequently in CIN III and overt carcinoma the more basally oriented low copy number, speckled, integrative pattern prevails. Fig. 4 HPV Copy Number and Disease Progression A. HPV and Cervical Cancers B. HPV Infection and Disease Progression Virus vs. Disease 1000 Normal Cytology Transformation Immortalization HPV Copies per cell 50 ASC LSIL HSIL Condyloma CIN I CIN II CIN III SCCA 1 Infection Acute Infection Disease progression Neoplasia Cancer 6

7 III. Representative Clinical Case Materials Following is a portfolio of cervical biopsies first diagnosed morphologically by Hematoxylin and Eosin (H&E) staining and then stained with INFORM HPV Probes for Family 16 and/or Family 6 HPV. Included are representative examples of normal cervical epithelial, CIN I, CIN II, CIN III, carcinoma and condyloma. A positive HPV result is judged when either the episomal or integrated pattern is found. The episomal pattern appears as a large homogeneous navy-blue precipitate within the nucleus. The integrative pattern is a discrete, stippled navy blue nuclear pattern within a field of cervical cells. As shown, the episomal pattern is generally prominent in the superficial keratinized region of the epithelium often within koilocytotic cells. The speckled nuclear integrative pattern is more often in more basal epithelial cells. Clinical Examples: A. Normal These cases are all cervical biopsies taken at colposcopy in the context of a preceding abnormal PAP or a visual colposcopic abnormality. As shown in Figure 5, these biopsies were all judged by H&E microscopy to be within normal limits without definitive pathologic alteration. In each case, the INFORM HPV III Family 16 Probe (B) was judged as negative with no evidence of either an episomal or integrative pattern present. In comparison with the negative reagent control, a very slight bluish haze is found. This trace staining is unrelated to HPV. In Cases 23 and 24, a common artifact is noted as a very superficial layer of navy-blue India Ink used at colposcopy to mark lesional tissue. Fig. 5 Normal Cervical Tissue Stained With INFORM HPV III Family 16 Probe (B) Case 22 Case 23 Case 24 Case 25 7

8 B. Cervical Intraepithelial Neoplasia (CIN) I These 3 cases illustrate, in Figure 6, the histopathologic and INFORM HPV III Family 16 Probe (B) staining characteristics of CIN I lesions. As shown, a predominance of the episomal nuclear staining in the superficial layers of the epithelial are the usual finding. Occasionally, a case of CIN I may have the mid-and basal-layer speckled, integrative pattern (see Case 7, Fig 2). Numerous studies have documented the high level of intraobserver and interobserver variability associated with the histopathologic diagnosis of CIN I. Upon adjudication in the ALTS trial, 41% of cases diagnosed on H&E as CIN I were down-graded to normal and 13% were upgraded to CIN II and CIN III 10. The biologic potential of CIN I lesions is characterized by high rates of spontaneous regression and low rates of progression to cancer. The poor reproducibility and uncertain biologic potential of CIN I have made the management of women with CIN I problematic. Recent evidence 2,3,5,11 suggests the identification of integrated HPV in the basal epithelium by means of in situ hybridization may distinguish patients with histologic CIN I who are at greater risk for the development of high-grade lesions. Fig. 6 CIN I Lesional Tissue Stained With INFORM HPV III Family 16 Probe (B) Case 26 (A): H&E Case 26 (B): HPV Case 27: HPV Case 28: HPV 8

9 C. Cervical Intraepithelial Neoplasia (CIN) II / III In contrast with the predominance of the episomal pattern in CIN I, the majority of CIN II / III cases (Figure 7) illustrate two patterns of HPV positivity. These include the prominent globular episomal staining found notably in the superficial epithelial cells. These represent the infective, exfoliated form, which is involved in subsequent disease transmission. Further, below in the epithelium, are found the epithelial cells with an integrative pattern of staining. These include cells from the mid-level to basal-level epithelial cells, which are thought to represent the sites of HPV-clonal integration into host cells. The adjacent stromal cells, endothelial cells, and lymphocytes are appropriately negative. As illustrated in Case 32, some CIN III lesions may contain only the integrative pattern with very low viral copy number. In this instance only one integration site per epithelial nucleus is observed. Fig. 7 CIN II/III Lesional Tissue Stained With INFORM HPV II Family 16 Probe (B) Case 29 Case 30 Case 31 Case 32 Case 33 Case 34 9

10 D. Squamous Cell Carcinoma These cases of invasive cervical squamous carcinoma (Figure 8) demonstrate nuclear HPV integrative pattern positivity in the neoplastic epithelial cell nuclei. While invasive cervical carcinoma may show two patterns of staining, both episomal and integrative, the majority of cervical carcinoma cases have a very low viral copy number (as documented in the literature), which manifest in tissue section ISH as the prominence of the integrated pattern of nuclear staining. As shown in Cases 35 and 36, the integrative pattern may often be the sole staining found in the neoplastic cells. Notice in the two cases illustrated the viral copy number and number of integration sites per nucleus is very similar to that observed within HeLa nuclei within the cell line control slide (see Figure 10). The adjacent stromal, lymphocyte, and endothelial cells are negative. Fig. 8 Cervical Carcinoma Lesional Tissue Stained With INFORM HPV III Family 16 Probe (B) Case 35 (A) Case 35 (B) Case 35 (C) Case 36 (A) Case 36 (B) Case 36 (C) 10

11 E. Condyloma Condyloma are superficial wart-like lesions found within the epithelium of the cervix and found in association with specific HPV genotypes (e.g. HPV 6 and 11). These HPV 6/11-associated lesions are expectedly negative for INFORM HPV III Family 16 Probe (B) (see Fig 9, Case 37 (B)) and positive for INFORM HPV II Family 6 Probe, as shown in Figure 10 (Case 37 and Case 38). The staining patterns in Cases 37 and 38 speak to the specificity of the INFORM HPV Family 16 and Family 6 Probes. Fig. 9 Condyloma Stained With INFORM HPV III Family 16 (B) and HPV II Family 6 Probes Case 37 (A): H&E Case 37 (B): INFORM HPV III Family 16 Probe (B) Case 37 (C): INFORM HPV II Family 6 Probe (B) Case 38: INFORM HPV II Family 6 Probe 11

12 IV. Use of Control Slides for System Quality Control A. Staining Patterns of Episomal and Integrated HPV The determination of a true negative and/or positive HPV INFORM ISH result requires, in the same run, a positive control slide such as a known HPV-positive control slide (see Figure 11) or an index case with an integrative-only pattern (see Figure 10). The appropriate positive integrative nuclear pattern is found in both CaSki and HeLa cells and absent in HPV negative cells. The CaSki cells are HPV 16 genotype cells with abundant copy number ( copies/cell). HeLa cells are HPV 18 genotype cells with lower viral copy number (10-50 copies/cell). The HeLa cell line in particular serves as a sensitivity control for the low level integrative staining pattern, which may be found in some CIN III (Figure 7) and in most invasive cervical carcinomas (Figure 8 and 10). The HPV-negative cells serve as an important indicator of inappropriate noise in the HPV assay. The importance of using a patient sample index case is well illustrated by Case 40 (see Figure 10). This patient sample of cervical carcinoma has a HeLa-like level of HPV expression and the multiple blocks available allow the use of either a same-slide or same-run control from a constant source for extended time. Fig. 10 Patient Index Case Control Samples Fig. 11 CaSki-like Case: Case 39 HeLa-like Case: Case 40 CaSki HeLa Negative C33 (Negative) + + CaSki HeLa Negative A. HPV 3 in 1 System Control Slide B. HPV Cell Lines Stained With HPV III Family 16 Probe (B) 12

13 V. Alu Positive Control Probe II for Tissue Qualification Specifically, the Alu Positive Control Probe II detects Alu repeats. A positive nuclear signal within epithelial and non-epithelial cells confirms the tissue sample contains intact DNA (Figures 12 and 13). A negative Alu Positive Control Probe II indicates loss of DNA intactness probably related either to tissue handling and/or tissue fixation. The Alu Positive Control probe serves as the equivalent of the housekeeping gene control used in PCR assays. Accordingly, like PCR, if DNA intactness is lost, a negative result may not be true and study of additional lesional tissue is necessitated. Figures 12 and 13 illustrate two clinically relevant examples of this assay. In Case 41, the Alu or DNA positivity is stronger with cell conditioning than without cell conditioning, indicating the importance of the unmasking of DNA by heat, ph, or enzymes. In Cases 42 and 43 are shown the relationship between Alu or DNA abundance and Alu signal and HPV assay signal. Fig. 12 DNA Positive Alu Control Slides Case 41 (A): Alu, no CC * - * CC = Cell Conditioning Case 41 (B): Alu with CC Fig. 13 Genome Integrity and ISH Assay Case 42 (A) Case 42 (B) Case 43 (A) Case 43 (B) 13

14 Notice in Case 43 the nearly absent Alu ISH is mirrored by a nearly-absent HPV result. Thus, the Alu ISH probe may be used to optimize the conditions for detection of HPV DNA allowing selection of ideal DNA signal preservation relative to cell conditioning or denaturation conditions. Finally, the Alu ISH probe may prove especially useful when there is an unexpected HPV-negative result in the face of lesional tissue (eg CIN I, II, III). In this instance, the Alu ISH assay might be absent or nearly absent establishing the lack of DNA preservation as an explanation of the unexpected negative assay result (Figure 13). The finding of a positive Alu ISH result, while indicating the intactness of biopsy DNA, does not establish DNA accessibility or openness related to fixation method or assay sensitivity. Accordingly while DNA may be intact and accessible for hybridization with neutral buffered formalin, it may be intact but not accessible with certain fixatives (Figure 14). VI. Fixation The Ventana-validated assay was developed utilizing tissue fixed in 10% neutral buffered formalin. Artificial tumors generated using the SiHa characterized human cell line (1-2 copies HPV 16 per nucleus) were fixed in a variety of fixatives for eighteen hours, two days, or five days. Tissue was prepared in 5μm sections and stained using HPV III Family 16 Probe (B) with extended cell conditioning and ISH protease 3 for four minutes. Figure 14 illustrates the ability of the Ventana validated assay to detect HPV in differentially fixed tissue. Results show HPV staining is robust in Neutral Buffered Formalin and Zinc Formalin fixed tissues; no degradation of signal or loss of antigen unmasking is noted for fixation times from eighteen hours to five days. In contrast, Prefer and Bouins fixatives show different levels of detection among the times tested when compared to Neutral Buffered Formalin. Less than optimal tissue acquisition, fixation and storage are major factors in the ability to detect HPV signal for microscopic interpretation. Fig. 14 HPV In Situ Hybridization Performance in SiHa Cell Lines NBF Zinc Formalin Prefer Bouin s Tissue Fixation Length 5 Days 2 Days 18 Hours 14

15 VII. Interpreting Artifacts A. Overdigestion Artifacts As illustrated in Figure 15, use of overly strong amounts of protease or prolonged protease treatment may result in a loss of tissue integrity making interpretation of lesional tissue difficult. B. Leukocyte-associated Artifacts Cytoplasmic staining of leukocytes, as shown in Figure 15, occurs frequently. This non-specific dense cytoplasm staining is unrelated to the DNA probes. It is associated with the secondary antibodies and/or bioconjugates reacting nonspecifically with cytoplasmic components. The localization in the cytoplasm, and not the nuclei, of both polymorphonuclear (PMNs) leukocytes and eosinophils indicates a non-specific, non-viral-associated artifact. Occasionally acute cervicitis with an abundance of PMNs is seen. The consequent artifactual staining is readily perceived as non-specific as the signal is found in the cytoplasm of PMNs and not in the nuclei of epithelial cells. Note that the true positive integrative pattern of HPV staining is also found in the epithelial cells of Case 46. Fig. 15 Artifacts With INFORM HPV III Family 16 Probe (B) Case 44 (A): Weak Protease 2 Case 45: PMN Artifacts Case 44 (B): Strong Protease 1 Case 46: PMN Artifact 15

16 C. Drying Artifacts Rarely, liquid reactants (buffers and liquid coverslip) may wick off the slide resulting in focal drying artifact. This may result in focal deposition of chromogen (eg NBT-BCIP complex) resulting in either a pool or band of blue dye (see Figure 16). Fig. 16 Artifacts With INFORM HPV III Family 16 Probe (B) Case 47 Case 48 Case 49 Case 50 16

17 D. Chromogen Precipitate Artifact Rarely, the NBT-BCIP chromogen may discretely precipitate resulting in irregular, meteorite-like dark blue foci of dye (see Figure 16). These burr-like objects are notably found above the plane of focus of the tissue surface, in contrast with the true episomal staining with smooth globular navy-blue staining, which is within the focal plane of the epithelial nucleus. Rarely the NBT-BCIP chromogen may precipitate in crystalline form (see Figure 17). This artifact is caused specifically by inadequate dehydration prior to cover-slipping. Fig. 17 Chromogen Precipitate Artifact: Case 51 17

18 E. Nuclear Artifact Two separate nuclear artifacts have been observed as rarities. First, a pale blue staining of nucleoli may be noted (see Figure 18). This phenomenon is not a virus-associated phenomenon but most probably reflects weak cross-hybridization with RNA under certain fixation and cell conditioning circumstances. As illustrated, this phenomenon characteristically occurs in all nucleoli, including both epithelial and non-epethelial cells. Second, stippled nuclear and/or cytoplasmic staining may occur in a blotchy pattern within lymphocytes, fibroblasts, and some endothelial cells (see Figure 19). This artifact has no viral association and, again, may reflect weak cross-hybridization with RNA under certain circumstance. The presence of this phenomena in lymphomal and stromal cells indicates non-specific staining and in the extreme may preclude diagnostic interpretation. Fig. 18 Nuclear Artifact: Case 52 Fig. 19 Nuclear Artifact: Case 53 18

19 VIII. Bibliography 1 Cooper K, Evans M, Mount S. Biology and evolution of cervical squamous intraepithelial lesions: a hypothesis with diagnostic prognostic implications. Advances in Anatomic Pathology 2003; 10(4): Lizard G, Roignot P, Brunet-Lecomte P, Chardonnet Y. Morphological analysis of in situ hybridization signals in cervical intraepithelial neoplasia containing human papillomavirus type 16 or 18: relationship with histological grade and DNA content. Cytometry 1998;34: Cooper J, Herrington CS, Stickland JE, Evans MF, McGee JOD. Episomal and integrated human papillomavirus in cervical neoplasia shown by non-isotopic in situ hybridization. J Clin Pathol 1991;44: Sano T, Hikino T, Niwa Y, Kashiwabara K, Oyama T, Fududa T, Nakajima T. In situ hybridization with biotinylated tyramide amplification: detection of human papillomavirus DNA in cervical neoplastic lesions. Mod Pathol 1998; 11: Evans ME, Mount SL, Beatty BG, Cooper K. Biotinyl-tyramide-based in situ hybridization signal patterns distinguish human papillomavirus type and grade of cervical intraepithelial neoplasia, Mod Pathol 2002; 15: Graf AH, Cheung AL, Hauser-Kornberger C, Dandachi N, Gubbs RR, Dietze O, Hacker GW. Clinical relevance of HPV 16/18 testing methods in cervical squamous cell carcinoma. Appl Immunohistochem Mol Morphol, 2000; 8: Nuovo GJ. The role of human papillomavirus in gynecologic diseases. In Advances in Pathology and Laboratory Medicine, vol. 8, 1995, Mosby-Year Book, Inc 8 Qureshi MN, Rudelli RD, Tubbs RR, Biscotti CV, Layfield LJ. Role of HPV DNA testing in predicting cervical intraepithelial lesions: comparison of HC HPV and ISH HPV. Diagnostic Cytopathology 2003; 29: Wright TC, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ Consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol, 2003; 189: Stoler M, Schiffman M, Interobserver Reproducibility of Cervical Cytologic and Histologic Interpretations, JAMA 2001, 285: Peitsaro P, Johansson B, Syrjanen S. Integrated human papillomavirus type 16 is frequently found in cervical cancer precursors as demonstrated by a novel quantitative real-time PCR technique. J Clin Microbiology 2002;40(3) Tranabloc P, Metaplasia and High Grade CIN, Diagnostic Difficulties. Gynecol Obstet Fertil ;30: Atlas of Diagnostic Immunohistopathology, L. True, ed., Lippincott 1990, pg ACOG Practice Bulletin No. 45, Cervical Cytology Screening. Clinical Management Guidelines for Obstetrician-Gynecologists. August Guidance for the Submission of Immunohistochemistry Applications to the FDA, June 3, Division of Clinical Laboratory Devices, Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration 16 Review Criteria for In Vitro Diagnostic Devices that Utilize Cytogenetic In Situ Hybridization Technology for the Detection of Human Genetic Mutations (Germ Line and Somatic). Draft Version: February 15, Page 2. Division of Clinical Laboratory Devices, Office of Device Evaluation, Center for Devices and Radiological Health, Food and Drug Administration 17 Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJF, Meijer CJLM, for the International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic Classification of Human Papillomavirus Types Associated with Cervical Caner. N Engl J Med 2003, 348;6. 18 Schiffman MH, Bauer HN, Hoover RN, Glass AG, Cadell DM, Rush BB, Scott DR, Sherman ME, Kurman RJ, Wacholder S, Stanton CK, Manos MM. Epidemiologic Evidence Showing That Human Papillomavirus Infection Causes Most Cervical Intraepithelial Neoplasia. J Natl Cancer Inst, 1993, 85,: Klase R, Woerner SM, Ridder R, Wentzensen N, Duerst M, Schneider A, Lotz B, Melsheimer P, von Knebel Doeberitz M. Detection of High-Risk Cervical Intraepithelial Neoplasia and Cervical Cancer by Amplification of Transcripts Derived from Integrated Papillomavirus Oncogenes. Cancer Res, 1999, 59: Stoler MH, Rhodes CR, Whitbeck A, Wolinsky SM, Chow LT, Broker TR. Human Papillomavirus Type 16 and 18 Gene Expression in Cervical Neoplasias. Hum Pathol, Feb 1992; 23: Nuovo GJ. Detection of Human Papillomavirus in Papanicolaou Smears: Correlation With Pathologic Findings and Clinical Outcome. Diagn Mol Pathol, June 1998, 7: Herrington CS, Anderson SM, Bauer HM, Troncone G, de Angelis ML, Noell H, Chimera JA, Van Eyck, SL, McGee J O D. Comparative analysis of human papillomavirus detection by PCR and non-isotopic in situ hybridization. J Clin Pathol 1995; 48: Wright TC, Schiffman M. Adding a Test for Human Papillomavirus DNA to Cervical-Cancer Screening. N Engl J Med, 2003, 348;6. 24 Cooper K, McGee J O D. Human papillomavirus, integration and cervical carcinogenesis: a clinicopathological perspective. J Clin Pathol Mol Pathol 1997; 50: Unger ER, Vernon SD, Lee DR, Miller DL, Reeves WC. Detection of Human Papillomavirus in Archival Tissues: Comparison of In Situ Hybridization and Polymerase Chain Reaction. J Histochem Cytochem, 46: , Vernon SD, Unger ER, Williams D. Comparison of Human Papillomavirus Detection and Typing by Cycle Sequencing, Line Blotting, and Hybrid Capture. J Clin Microbiol, 38: , Unger ER, Hammer ML, Chenggis ML. Comparison of 35S and Biotin as Labels for In Situ Hybridization: Use of an HPV Model System1.. J Histochem Cytochem, 39: , Unger ER, Lee DR. In Situ Hybridization: Principles and Diagnostic Applications in Infection. J Histotech, 18:203:209, Unger, ER, Vernon SD, Thoms WW, Nisenbaum R, Spann CO, Horowitz IR, Icenogle JP, Reeves WC. Human Papillomavirus and Disease-Free Survival in FIGO Stage Ib Cervical Cancer. J Infect Dis, 172: , Vernon SD, Unger ER, Miller DL, Lee DR, Reeves WC. Association of Human Papillomavirus Type 16 Integration in the E2 Gene with Poor Disease-Free Survival from Cervical Cancer. Int J Cancer (Pred Oncol): 74, 50-56, Unger, ER. In Situ Diagnosis of Human Papillomaviruses. Clin Lab Med, 20:289:301,

20 Corporate Offices North America Ventana Medical Systems, Inc E. Innovation Park Drive Tucson, Arizona U.S.A. +1 (520) (800) (U.S.) Europe Ventana Medical Systems, S.A. Parc d'innovation - BP Rue G. de Kaysersberg F Illkirch CEDEX France +33 (0) Australia, New Zealand Ventana Medical Systems Pty Ltd 5/39 Grand Boulevard Montmorency VIC 3094 Australia +61 (0) MDCI Ltd. Arundel House 1 Liverpool Gardens Worthing West Sussex BN11 1SL U.K Ventana Medical Systems, Inc. Printed in U.S.A. N A VENTANA, INFORM, and BenchMark are registered trademarks of Ventana Medical Systems, Inc. Innovations in Science and Medicine

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