title: Biological relevance of human papillomaviruses in vulvar cancer.
abstract: The carcinogenic role of high-risk human papillomavirus (HR-HPV) types in the increasing subset of vulvar intraepithelial neoplasia and vulvar cancer in young women has been established. However, the actual number of vulvar cancer cases attributed to HPV is still imprecisely defined. In an attempt to provide a more precise definition of HPV-driven vulvar cancer, we performed HPV-type-specific E6*I mRNA analyses available for 20 HR-/possible HR (pHR)-HPV types, on tissue samples from 447 cases of vulvar cancer. HPV DNA genotyping was performed using SPF10-LiPA25assay due to its high sensitivity in formalin-fixed paraffin-embedded tissues. Data on p16INK4aexpression was available for comparative analysis via kappa statistics. The use of highly sensitive assays covering the detection of HPV mRNA in a broad spectrum of mucosal HPV types resulted in the detection of viral transcripts in 87% of HPV DNA+ vulvar cancers. Overall concordance between HPV mRNA+ and p16INK4aupregulation (strong, diffuse immunostaining in >25% of tumor cells) was 92% (K=0.625, 95% confidence interval (CI)=0.531-0.719). Among these cases, 83% were concordant pairs of HPV mRNA+ and p16INK4a+ and 9% were concordant pairs of HPV mRNA- and p16INK4a-. Our data confirm the biological role of HR-/pHR-HPV types in the great majority of HPV DNA+ vulvar cancers, resulting in an HPV-attributable fraction of at least 21% worldwide. Most HPV DNA+ vulvar cancers were associated with HPV16 (85%), but a causative role for other, less frequently occurring mucosal HPV types (HPV26, 66, 67, 68, 70 and 73) was also confirmed at the mRNA level for the first time. These findings should be taken into consideration for future screening options as HPV-associated vulvar preneoplastic lesions have increased in incidence in younger women and require different treatment than vulvar lesions that develop from rare autoimmune-related mechanisms in older women.
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Gordana
authors.initials: G
authors.lastname: Halec
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Alemany
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Quiros
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Omar
authors.initials: O
authors.lastname: Clavero
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Höfler
authors.affiliation: General Hospital d'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Alejo
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Quint
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Bosch
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: de Sanjose
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology*; D014846:Vulvar Neoplasms / Q000473:pathology / Q000821:virology*