title: Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches.
abstract: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell carcinoma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential clinical significance of PD-L1 expression in penile SqCC.
  
  
  
  Using an anti-PD-L1 primary antibody (clone 5H1), immunohistochemistry was carried out on whole tumor sections from 37 patients with penile SqCC treated at our institution between 2005 and 2013. PD-L1-positive tumors were defined as those with membranous staining in ≥5% of tumor cells. Association between PD-L1 expression and clinicopathologic parameters was examined using Fisher's exact test. Correlation between PD-L1 expression in primary tumors and matched metastases was assessed using the Spearman rank correlation coefficient (ρ). The difference in cancer-specific mortality between PD-L1-positive and -negative groups was examined using the log-rank test.
  
  
  
  Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (ρ = 0.72; 0.032 < P < 0.036). Primary tumor PD-L1 expression was significantly associated with usual type histology (P = 0.040) and regional lymph node metastasis (P = 0.024), as well as decreased cancer-specific survival (P = 0.011).
  
  
  
  The majority of primary penile SqCC tumors express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapeutics in patients with advanced penile SqCC.
authors.affiliation: Department of Pathology, University of Michigan Health System.
authors.forename: A M
authors.initials: AM
authors.lastname: Udager
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Michigan Health System.
authors.forename: S L
authors.initials: SL
authors.lastname: Skala
authors.affiliation: Department of Pathology, University of Michigan Health System.
authors.forename: M J
authors.initials: MJ
authors.lastname: Magers
authors.affiliation: Department of Pathology, University of Michigan Health System.
authors.forename: A S
authors.initials: AS
authors.lastname: McDaniel
authors.affiliation: Department of Radiation Oncology Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor.
authors.forename: D E
authors.initials: DE
authors.lastname: Spratt
authors.affiliation: Department of Radiation Oncology Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor.
authors.forename: F Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Departments of Urology.
authors.forename: J
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Departments of Urology.
authors.forename: X
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pathology, University of Michigan Health System.
authors.forename: K L
authors.initials: KL
authors.lastname: Fields
authors.affiliation: Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System.
authors.forename: T M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System.
authors.forename: G S
authors.initials: GS
authors.lastname: Palapattu
authors.affiliation: Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Weizer
authors.affiliation: Department of Pathology, University of Michigan Health System Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Departments of Urology Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System Michigan Center for Translational Pathology.
authors.forename: A M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Howard Hughes Medical Institute, Ann Arbor, USA.
authors.forename: A
authors.initials: A
authors.lastname: Alva
authors.affiliation: Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System.
authors.forename: J S
authors.initials: JS
authors.lastname: Montgomery
authors.affiliation: Department of Pathology, University of Michigan Health System Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Departments of Urology Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System.
authors.forename: S A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology, University of Michigan Health System Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor Departments of Urology mrohit@med.umich.edu.
authors.forename: R
authors.initials: R
authors.lastname: Mehra
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010412:Penile Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D012307:Risk Factors
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human
keywords: PD-L1; immunohistochemistry; immunotherapy; penile cancer; squamous cell carcinoma