title: p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study.
abstract: OBJECTIVE
  We assessed the prognostic role of p16(INK4a) expression in penile cancer with respect to cancer specific survival.
  
  
  METHODS
  Based on a multi-institutional collaboration wax embedded tissues from 92 surgically treated patients, including 27 with total and 65 with partial penectomy, were retrospectively evaluated. After a central histopathological review by 1 pathologist a tissue microarray was constructed for p16(INK4a) immunostaining. Two independent pathologists evaluated p16(INK4a) expression, which was correlated with cancer specific survival. The κ statistic was used to assess interobserver variability. Univariate and multivariate Cox proportional hazards analysis was applied to assess the independent effects of prognostic factors on cancer specific survival during a median postoperative followup of 32 months (IQR 6-66).
  
  
  RESULTS
  The κ statistic revealed excellent interobserver agreement (κ 0.934, p <0.001). Two and 5-year cancer specific survival rates for the entire study cohort were 86% and 74%, respectively. The 2 and 5-year rates for patients without and with p16(INK4a) expression differed significantly (73% and 57% vs 95% and 85%, respectively, p = 0.011). Univariate analysis revealed p16(INK4a) expression as a significant prognostic factor with respect to cancer specific survival (p = 0.018). Multivariate analysis identified koilocytosis (HR 0.24, 95% CI 0.07-0.83, p = 0.024), p16(INK4a) expression (HR 0.44, 95% CI 0.23-0.84, p = 0.013), and histological stage (HR 3.54, 95% CI 1.88-6.67, p <0.001) and grade (HR 2.47, 95% CI 1.00-6.09, p = 0.049) as independent prognostic factors for cancer specific survival.
  
  
  CONCLUSIONS
  Results show that p16(INK4a) seems to be a prognostic parameter for primary invasive penile cancer with excellent interobserver reproducibility. At pathology laboratories without antibodies against p16(INK4a) conventional histological determination of koilocytosis by the pathologist also appears to provide important prognostic information for cancer specific survival.
authors.affiliation: Institute of Pathology, HELIOS Clinic Bad Saarow, Bad Saarow, Germany. sven.gunia@helios-kliniken.de
authors.forename: Sven
authors.initials: S
authors.lastname: Gunia
authors.forename: Andreas
authors.initials: A
authors.lastname: Erbersdobler
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Hakenberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Koch
authors.forename: Matthias
authors.initials: M
authors.lastname: May
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010412:Penile Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16