title: Prognostic importance of human papillomavirus (HPV) and p16 positivity in squamous cell carcinoma of the vulva treated with radiotherapy.
abstract: HPV status is an important prognostic factor for patients with oropharyngeal, anal and cervical cancers treated with radiotherapy. This study evaluates the association between HPV and p16 status and outcome in a radiation-treated cohort with vulvar squamous cell carcinoma (SCC).
  
  
  
  Patients with vulvar SCC who received radiotherapy with or without surgical resection between 1985 and 2011 were identified retrospectively. Immunostaining for p16 and multiplex PCR for HPV genotyping were performed using archival tumor tissue from 57 patients. Actuarial estimates of PFS, OS and in-field recurrence were calculated using the Kaplan-Meier method. Cox proportional hazards models were used for multivariable analysis. Median follow-up was 58months among the 57 patients with an available tumor specimen.
  
  
  
  HPV prevalence was implied in 37% by (diffuse linear) p16 immunostaining and confirmed in 27% by HPV PCR with good agreement (κ=0.7). HPV-16 was identified in 80% of HPV-positive tumors. Women with p16-positive tumors had significantly higher 5-year PFS (65% vs. 16%, p<0.01) and OS (65% vs. 22%, p=0.01) rates, as well as lower in-field relapse rates (19% vs. 75%, p<0.01) compared to those with p16-negative disease. On multivariable analysis adjusted for age and stage, p16 positivity was significantly associated with better PFS (HR 0.4, 95% CI 0.2-0.9) and lower rates of in-field relapse (HR 0.2, 95% CI 0.06-0.6). Results were similar when analyzed by HPV DNA status.
  
  
  
  In this study, the presence of HPV or its surrogate of p16 immunostaining was an independent prognostic factor for in-field relapse and survival in women with vulvar SCC treated with radiotherapy. This finding warrants validation in larger cohorts or the prospective setting.
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. Electronic address: llee@lroc.harvard.edu.
authors.forename: Larissa J
authors.initials: LJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Brooke
authors.initials: B
authors.lastname: Howitt
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Catalano
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tanaka
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Rita
authors.initials: R
authors.lastname: Murphy
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cimbak
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: DeMaria
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Bu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Crum
authors.affiliation: Department of Gynecologic Oncology, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Horowitz
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matulonis
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States.
authors.forename: Akila N
authors.initials: AN
authors.lastname: Viswanathan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy* / Q000821:virology; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000096:biosynthesis*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012189:Retrospective Studies; D016896:Treatment Outcome; D014846:Vulvar Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000821:virology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral
keywords: Human papillomavirus; Radiotherapy; Vulvar cancer; p16