title: Nonendemic HPV-positive nasopharyngeal carcinoma: association with poor prognosis.
abstract: OBJECTIVE
  To investigate the relationship between human papillomavirus (HPV) and Epstein-Barr virus (EBV) in nonendemic nasopharyngeal carcinoma (NPC) and assess the prognostic implications of viral status.
  
  
  METHODS
  Paraffin-embedded tumor specimens from 62 patients with primary NPC diagnosed between 1985 and 2011 were analyzed for EBV and high-risk HPV. EBV status was determined by the use of in situ hybridization for EBV encoded RNA. HPV status was assessed with p16 immunohistochemistry and multiplex polymerase chain reaction MassArray for determination of HPV type. Proportional hazards models were used to compare the risk of death among patients as stratified by viral status.
  
  
  RESULTS
  Of 61 evaluable tumors, 26 (43%) were EBV-positive/HPV-negative, 18 (30%) were HPV-positive/EBV-negative, and 17 (28%) were EBV/HPV-negative. EBV and HPV infection was mutually exclusive. HPV positivity was significantly correlated with World Health Organization grade 2 tumors, older age, and smoking (all P<.001). The racial distribution of the study population was 74% white, 15% African American, and 11% Asian/Middle Eastern. Among HPV-positive patients, 94% were white. At a median follow-up time of 7 years, HPV-positive and EBV/HPV-negative tumors exhibited worse outcomes than did EBV-positive tumors, including decreased overall survival (hazard ratio [HR] 2.98, P=.01; and HR 3.89, P=.002), progression-free survival (HR 2.55, P=.02; and HR 4.04, P<.001), and locoregional control (HR 4.01, P=.03; and HR 6.87, P=.001).
  
  
  CONCLUSIONS
  In our Midwestern population, high-risk HPV infection may play an etiologic role in the development of nonendemic, EBV-negative NPC. Compared with EBV-positive NPC, HPV-positive and EBV/HPV-negative NPC are associated with worse outcomes. A larger confirmatory study is needed to validate these findings.
authors: Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan. Electronic address: stenmark@med.umich.edu.
authors: Matthew H
authors: MH
authors: Stenmark
authors: Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Jonathan B
authors: JB
authors: McHugh
authors: Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan; Department of Biostatistics, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Matthew
authors: M
authors: Schipper
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Heather M
authors: HM
authors: Walline
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Christine
authors: C
authors: Komarck
authors: Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Felix Y
authors: FY
authors: Feng
authors: Department of Medical Oncology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Francis P
authors: FP
authors: Worden
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Gregory T
authors: GT
authors: Wolf
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Douglas B
authors: DB
authors: Chepeha
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Mark E
authors: ME
authors: Prince
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Carol R
authors: CR
authors: Bradford
authors: Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Suresh K
authors: SK
authors: Mukherji
authors: Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Avraham
authors: A
authors: Eisbruch
authors: Department of Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan.
authors: Thomas E
authors: TE
authors: Carey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000208:ethnology / Q000401:mortality / Q000821:virology*; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000208:ethnology / Q000401:mortality / Q000821:virology*; D011379:Prognosis; D012367:RNA, Viral / Q000302:isolation & purification; D055815:Young Adult
chemical_list: D012367:RNA, Viral