title: Epithelial-mesenchymal transition (EMT) phenotype at invasion front of squamous cell carcinoma of the penis influences oncological outcomes.
abstract: Our aims were to evaluate epithelial-mesenchymal transition (EMT) as a useful prognostic marker in penile carcinoma (PC), and establish an objective criterion to define EMT in PC specimens.
  
  
  
  A total of 149 consecutive cases surgically treated for PC were retrospectively selected. E-cadherin (E-CAD) and vimentin immunohistochemical expressions were evaluated. A combined analysis was performed using both markers to determine EMT status. To establish a normal control to E-CAD expression, we included 14 cases from circumcisions from patients without any neoplastic disease and 77 cases of tumor-free margins. The analyses of tumor samples were evaluated in 2 different areas of the tumor. The first one was in the tumor core. The second analyses were performed on the deepest infiltrative edge of the tumor, nominated invasion front. Cases were classified into EMT absent group, partial EMT group and complete EMT group. Overall survival (OS) and cancer-specific survival (CSS) were analyzed. Kaplan-Meier curves and the log-rank test were used. Cox proportional hazards model was used to determine which variables influenced survival.
  
  
  
  Tumor specimens presented a significant loss of expression of E-CAD when compared with normal epithelium. Vimentin expression in more than 10% of tumor cells was observed in 50 cases. EMT status was associated with histologic grade, pattern of invasion, lymph node metastasis, and perineural and vascular invasion. Further, 10-year OS and CSS rates in patients with presence and absence of complete EMT status were 38.0% and 55.6%; and 48.0% and 91.9%, respectively. EMT status significantly affected CSS and OS rates even after patients were grouped based on lymph node involvement status. The presence of complete EMT status was associated with both CSS and OS rates. Patients in the complete EMT group had a higher risk of death from cancer (hazard ratio = 7.6, P<0.001) and overall death (hazard ratio = 3.0, P<0.001).
  
  
  
  Our study represents an evidence of the prognostic effect of EMT in PC. We encourage the study of EMT markers in other centers to validate our findings and confirm its importance in such tumors.
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: da Cunha
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Maria José L
authors.initials: MJ
authors.lastname: Souza
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil. Electronic address: waltercosta@hotmail.com.
authors.forename: Walter Henriques
authors.initials: WH
authors.lastname: da Costa
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Amâncio
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Francisco Paulo
authors.initials: FP
authors.lastname: Fonseca
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Stenio de Cassio
authors.initials: Sde C
authors.lastname: Zequi
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Gustavo Cardoso
authors.initials: GC
authors.lastname: Guimarães
authors.affiliation: Urology Division, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Soares
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000556:secondary*; D016022:Case-Control Studies; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D010412:Penile Neoplasms / Q000378:metabolism / Q000473:pathology*; D010413:Penis / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D014746:Vimentin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D014746:Vimentin
keywords: Penile cancer; Penile carcinoma; Prognosis; Prognostic markers