title: Informed cytology for triaging HPV-positive women: substudy nested in the NTCC randomized controlled trial.
abstract: BACKGROUND
  Human papillomavirus (HPV)-based screening needs triage. In most randomized controlled trials (RCTs) on HPV testing with cytological triage, cytology interpretation has been blind to HPV status.
  
  
  METHODS
  Women age 25 to 60 years enrolled in the New Technology in Cervical Cancer (NTCC) RCT comparing HPV testing with cytology were referred to colposcopy if HPV positive and, if no cervical intraepithelial neoplasia (CIN) was detected, followed up until HPV negativity. Cytological slides taken at the first colposcopy were retrieved and independently interpreted by an external laboratory, which was only aware of patients' HPV positivity. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were computed for histologically proven CIN2+ with HPV status-informed cytology for women with a determination of atypical squamous cells of undetermined significance (ASCUS) or more severe. All statistical tests were two-sided.
  
  
  RESULTS
  Among HPV-positive women, informed cytology had cross-sectional sensitivity, specificity, PPV and 1-NPV for CIN2+ of 85.6% (95% confidence interval [CI] = 76.6 to 92.1), 65.9% (95% CI = 63.1 to 68.6), 16.2% (95% CI = 13.0 to 19.8), and 1.7 (95% CI = 0.9 to 2.8), respectively. Cytology was also associated with subsequent risk of newly diagnosed CIN2+ and CIN3+. The cross-sectional relative sensitivity for CIN2+ vs blind cytology obtained by referring to colposcopy and following up only HPV positive women who had HPV status-informed cytology greater than or equal to ASCUS was 1.58 (95% CI = 1.22 to 2.01), while the corresponding relative referral to colposcopy was 0.95 (95% CI = 0.86 to 1.04).
  
  
  CONCLUSIONS
  Cytology informed of HPV positivity is more sensitive than blind cytology and could allow longer intervals before retesting HPV-positive, cytology-negative women.
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Christine
authors.initials: C
authors.lastname: Bergeron
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Paolo
authors.initials: P
authors.lastname: Giorgi-Rossi
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Frederic
authors.initials: F
authors.lastname: Cas
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Schiboni
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Bruno
authors.initials: B
authors.lastname: Ghiringhello
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Paolo
authors.initials: P
authors.lastname: Dalla Palma
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Daria
authors.initials: D
authors.lastname: Minucci
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Stefano
authors.initials: S
authors.lastname: Rosso
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Manuel
authors.initials: M
authors.lastname: Zorzi
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Carlo
authors.initials: C
authors.lastname: Naldoni
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Nereo
authors.initials: N
authors.lastname: Segnan
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR).
authors.forename: Massimo
authors.initials: M
authors.lastname: Confortini
authors.affiliation: Department of Pathology, Laboratoire Cerba, Cergy Pontoise France (CB, FC); Servizio Interaziendale Epidemiologia, AUSL Reggio Emilia, Italy (PGR); Department of Pathology, S. Giovanni Hospital, Rome, Italy (MLS); Laboratory Department University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (BG); Department of Pathology, S. Chiara Hospital, Trento, Italy (PDP); Women's Health Department, University Hospital, Padua, Italy (DM); Veneto Oncology Institute IRCCS, Padua, Italy (MZ); Emilia-Romagna Region, Bologna, Italy (CN); Laboratory of Preventive Oncology, Institute for Cancer Study and Prevention (ISPO), Florence (MC); Department of Cancer Screening, Center for Epidemiology and Prevention in Oncology (CPO), University Hospital "Città della Salute e della Scienza di Torino," Turin, Italy (GR, NS, SR). guglielmo.ronco@cpo.it.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Ronco
mesh_terms: D000328:Adult; D052685:Alphapapillomavirus; D065309:Atypical Squamous Cells of the Cervix; D003127:Colposcopy; D005260:Female; D006801:Humans; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis*; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D014218:Triage / Q000379:methods; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000821:virology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000821:virology