title: Cell cycle and/or proliferation markers: what is the best method to discriminate cervical high-grade lesions?
abstract: The aim of this study on a series of biopsies diagnosed as normal, metaplastic, low-grade squamous intraepithelial lesions (LSILs), and high-grade squamous intraepithelial lesions (HSILs) was dual: to determine the chronology of cell cycle and proliferation abnormalities after human papillomavirus infection during the development of squamous intraepithelial lesions and to determine the best diagnostic indicator(s) linked to the appearance of an HSIL. Ninety-nine cervical biopsies, 18 normal, 9 with metaplastic changes, 29 LSIL, and 43 HSIL (23 cervical intraepithelial neoplasia 2 and 20 cervical intraepithelial neoplasia 3), were analyzed by image cytometry for DNA ploidy and p16INK4A determination, AgNOR counting, MIB-1, and ICBP90 immunostaining quantification. The human papillomavirus status had been previously determined on corresponding cytological smears with the Hybrid Capture II test. Suspect DNA profile and p16INK4A staining were the first significant events that preceded the increase of cell proliferation. Indeed, these markers were the best tests for the detection of a lesion, whatever its grade (positive predictive values of 90% and 100%, respectively). The presence of MIB-1- or ICBP90-positive cells in the upper two thirds of the epithelium was a very accurate feature to select HSIL (sensitivity, 100% for MIB-1) but with a low specificity. The sensitivity of a suspect DNA profile associated with a positive MIB-1 or ICPB90 immunostaining for the detection of an HSIL was, respectively, 92.8% and 92.7%; their specificities were 54.2% and 44%; their positive predictive values were 78% and 73%; their negative predictive values were 81.2% and 78.6%; and the global values were 78.8% and 74.3%. Thus, the most accurate test to distinguish an LSIL from an HSIL was the association of a suspect DNA profile and the presence of MIB-1- or ICBP90-positive cells in the upper two thirds of the epithelium.
authors.affiliation: Laboratoire Pol Bouin, Department of Histology and Cystology, Maison Blanche Hospital, 51092 Reims Cedex, France. mlorenzato@chu-reims.fr
authors.forename: Marianne
authors.initials: M
authors.lastname: Lorenzato
authors.forename: Stephanie
authors.initials: S
authors.lastname: Caudroy
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Evrard
authors.forename: Maryline
authors.initials: M
authors.lastname: Simon
authors.forename: Anne
authors.initials: A
authors.lastname: Durlach
authors.forename: Philippe
authors.initials: P
authors.lastname: Birembaut
authors.forename: Christine
authors.initials: C
authors.lastname: Clavel
mesh_terms: D000974:Antibodies, Antinuclear / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D034961:Antigens, Nuclear / Q000032:analysis; D014408:Biomarkers, Tumor; D001706:Biopsy; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000235:genetics; D015344:DNA Probes, HPV / Q000235:genetics; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D009687:Nuclear Proteins / Q000032:analysis; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000378:metabolism / Q000821:virology; D011003:Ploidies; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D044767:Ubiquitin-Protein Ligases; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery / Q000821:virology
chemical_list: D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015344:DNA Probes, HPV; C440408:MIB-1 antibody; D009687:Nuclear Proteins; C051963:nucleolar organizer region associated proteins; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases