title: High-risk human papillomavirus-positive lung cancer: molecular evidence for a pattern of pulmonary metastasis.
abstract: BACKGROUND
  Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital, and oropharyngeal cancers. Since a causal contribution of hrHPV infection to lung cancer (LC) is still a matter of debate, a comprehensive study was performed to delineate hrHPV involvement in LC, using a Dutch study population.
  
  
  METHODS
  Archival tissue specimens from 223 patients (145 men, 78 women, median age 65 years, range 27-87 years), who presented with cancer in the lungs, were subjected to GP5+/6+ polymerase chain reaction and p16 immunohistochemistry. The series included primary lung carcinomas of patients without a history of cancer (n = 175), primary lung carcinomas of patients with an unrelated cancer in the past (n = 36), and carcinomas with primary presentation in the lungs of which the origin (i.e., primary or metastasis) was equivocal at the time of diagnosis (n = 12). GP5+/6+ polymerase chain reaction/p16 double-positive carcinomas were subjected to HPV genotyping, HPVE7 transcript analysis, loss of heterozygosity analysis, and array-comparative genomic hybridization.
  
  
  RESULTS
  Whereas all primary lung carcinomas were hrHPV-negative (211 of 211, 100%), three hrHPV-positive equivocal carcinomas (3 of 12, 25%) were identified. These patients (1 male, 2 females) had a history of hrHPV-associated disease; one tonsillar and two cervical carcinomas. A clonal relationship between individual tumor pairs was supported by identical hrHPV genotype, pattern of p16 expression, HPVE7 mRNA expression, and genomic aberrations.
  
  
  CONCLUSIONS
  hrHPV presence in a tumor with primary presentation in the lungs signifies pulmonary metastasis from a primary hrHPV-positive cancer elsewhere in the body. No support was found for an attribution of hrHPV infection to the development of primary LC.
authors.affiliation: Department of Pathology, Academic Center for Dentistry Amsterdam (ACTA), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Robert A A
authors.initials: RA
authors.lastname: van Boerdonk
authors.forename: Johannes M A
authors.initials: JM
authors.lastname: Daniels
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bloemena
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
authors.forename: Katrien
authors.initials: K
authors.lastname: Grünberg
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary* / Q000821:virology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000556:secondary* / Q000821:virology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000556:secondary* / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000556:secondary* / Q000821:virology; D055028:Comparative Genomic Hybridization; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology* / Q000821:virology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral