title: Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status.
abstract: PD-L1 (programmed death ligand 1) inhibits T-cell function and prevents tumor eradication. This is facilitated by PD-L1 positive tumor cells and PD-L1 positive immune cells, and can be prevented by anti-PD-1 (programmed death 1)/PD-L1 immunotherapy. In advanced penile cancer there is a need for new therapeutic strategies. We investigated PD-L1 expression in penile cancers and compared PD-L1 expression with disease specific survival, lymph node metastases at diagnosis and high risk HPV status in a large patient cohort.
  
  
  
  A total of 213 primary tumors were immunohistochemically stained for PD-L1 and scored for tumor (percentage), stroma (binary) and PD-L1 positive tumor infiltrating macrophages. Additionally, PD-L1 positive tumors were scored for expression pattern, that is diffuse or predominantly present at the tumor-stroma margin.
  
  
  
  Staining was successful in 200 tumors, of which 75% were high risk HPV negative. Median followup was 62 months. Of 200 tumors 96 (48%) were PD-L1 positive (scored 1% or greater), of which 59 (62%) had a marginal expression pattern and 79 (82%) were high risk HPV negative (p = 0.03). Compared to PD-L1 negative tumors, the PD-L1 expression patterns had different prognostic values in the whole cohort as well as in the high risk HPV negative subgroup. On multivariable analyses a marginal expression pattern was associated with absent lymph node metastases (OR 0.4) while diffuse expression was associated with poor survival (HR 2.58). These results were more prominent in the high risk HPV negative subgroup (OR 0.25, HR 3.92).
  
  
  
  PD-L1 was expressed in 48% of penile carcinomas and mainly in high risk HPV negative tumors. The pattern of expression was a prognostic factor as marginal expression was associated with absent lymph node metastases and diffuse expression was associated with poor survival.
authors.affiliation: Department of Urological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: s.ottenhof@nki.nl.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Ottenhof
authors.affiliation: Department of Urological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Rosa S
authors.initials: RS
authors.lastname: Djajadiningrat
authors.affiliation: Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Helene H
authors.initials: HH
authors.lastname: Thygesen
authors.affiliation: Department of Urological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: Horenblas
authors.affiliation: Center Gynecological Oncology Amsterdam, Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism*; D015331:Cohort Studies; D006801:Humans; D008297:Male; D030361:Papillomavirus Infections / Q000150:complications* / Q000378:metabolism*; D010412:Penile Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000821:virology*; D011237:Predictive Value of Tests; D011379:Prognosis
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human
keywords: alphapapillomavirus; antigens; cd274; penile neoplasms; survival analysis; tumor escape