title: p16(INK4a) /Ki-67 dual labelling as a marker for the presence of high-grade cancer cells or disease progression in urinary cytopathology.
abstract: OBJECTIVE
  Overexpression of p16(INK4a) independent of the presence of E6-E7 oncoproteins of high-risk papillomaviruses has been identified in bladder carcinoma in situ lesions with or without concurrent papillary or invasive high-grade (HG) urothelial carcinoma. As p16(INK4a) and Ki-67 co-expression clearly indicates deregulation of the cell cycle, the aim of this study was to investigate the frequency of p16(INK4a) /Ki-67 dual labelling in urinary cytology samples.
  
  
  METHODS
  Immunolabelling was performed in demounted, destained Papanicolaou slides after ThinPrep(®) processing. A total of 84 urinary cytology samples (18 negative, 10 low grade, 19 atypical urothelial cells and 37 high grade) were analysed for p16(INK4a) /Ki-67 co-expression. We assessed underlying urothelial malignancy with cystoscopy, histopathology and follow-up data in every case.
  
  
  RESULTS
  Compared with raw histopathological results, p16 (INK4a) /Ki-67 dual labelling was observed in 48 out of 55 (87.3%) HG lesions and in 11 out of 29 (37.9%) negative, papillary urothelial neoplasia of low malignant potential or low-grade carcinomas (P = 0.05). All cases with high-grade/malignant cytology were dual labelled. Sixteen out of 17 (94.1%) carcinoma in situ cases and eight out of 14 (57.1%) cases with atypical urothelial cells matching with HG lesions were dual labelled. Extended follow-up allowed three cases of progression to be diagnosed in dual-labelled cases with negative/low-grade cytology results after a 9- to 11-months delay.
  
  
  CONCLUSIONS
  The data show that p16(INK4a) /Ki-67 co-expression allows most HG cancer cells to be detected initially and in the follow-up period. Additional studies are needed in order to determine whether dual labelling can be used as a triage tool for atypical urothelial cells in the urine.
authors.affiliation: Hospices Civils de Lyon, Centre de Pathologie Est, Hôpital Femme-Mère-Enfant, Bron Université Claude Bernard Lyon 1, Lyon Département de Biopathologie, Centre de Lutte Contre le Cancer Léon Bérard, Lyon Laboratoire MTM France, Jouy en Josas Centre de Pathologie Sud, Centre Hospitalier Lyon Sud, Pierre Bénite Service d'Anatomie et Cytologie Pathologiques, Hôpital Edouard Herriot, Lyon Service d'Urologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
authors.forename: E
authors.initials: E
authors.lastname: Piaton
authors.forename: A S
authors.initials: AS
authors.lastname: Advenier
authors.forename: C
authors.initials: C
authors.lastname: Carré
authors.forename: M
authors.initials: M
authors.lastname: Decaussin-Petrucci
authors.forename: F
authors.initials: F
authors.lastname: Mege-Lechevallier
authors.forename: A
authors.initials: A
authors.lastname: Ruffion
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000652:urine*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000652:urine*; D003581:Cytodiagnosis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000652:urine*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000302:isolation & purification; D011247:Pregnancy; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000473:pathology / Q000652:urine* / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen