title: Recurrent respiratory papillomatosis: HPV genotypes and risk of high-grade laryngeal neoplasia.
abstract: Patients with recurrent respiratory papillomatosis (RRP) in Norway treated between 1987 and 2009 were recruited to this cohort study. They were followed from disease onset and data recorded until January 2012. Here, we describe the distribution of human papillomavirus (HPV) genotypes, the prevalence of multiple HPV infections, and the risk of high-grade laryngeal neoplasia and respiratory tract invasive carcinoma in a large cohort of patients with RRP. We also examined whether HPV genotype, gender, age or clinical course are risk factors for this development. Clinical records and histological specimens were reviewed. Using formalin-fixed paraffin-embedded biopsies, HPV genotyping were performed by quantitative polymerase chain reaction assays identifying 15 HPV types. HPV-negative specimens were analyzed by metagenomic sequencing. Paraffin blocks were available in 224/238 patients. The DNA quality was approved in 221/224 cases. HPV DNA was detected in 207/221 patients and all were HPV 6 or HPV 11 positive, comprising HPV 6 in 133/207, HPV 11 in 40/207 cases and HPV 6/11 in 15/207 cases. Co-infection with one or two high-risk HPV types together with HPV 6 or HPV 11 was present in 19/207 patients. Metagenomic sequencing of 14 HPV-negative specimens revealed HPV 8 in one case. In total, 39/221 patients developed high-grade laryngeal neoplasia. 8/221 patients developed carcinoma of the respiratory tract (six patients with laryngeal carcinoma and two patients with lung carcinoma). High-grade laryngeal neoplasias were found more frequently in HPV-negative versus HPV-positive patients, (RR = 2.35, 95% CI 1.1, 4.99), as well as respiratory tract carcinomas (RR = 48, 95% CI 10.72, 214.91). In summary, the majority of RRP were associated with HPV 6 and/or 11. HPV-negative RRP biopsies occurred more frequently in adult-onset patients, and were associated with an increased risk of laryngeal neoplasia and carcinoma in the respiratory tract.
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, Oslo University Hospital and University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
authors.forename: Turid
authors.initials: T
authors.lastname: Omland
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Kathrine A
authors.initials: KA
authors.lastname: Lie
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, Oslo University Hospital and University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
authors.forename: Harriet
authors.initials: H
authors.lastname: Akre
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Lars Erik
authors.initials: LE
authors.lastname: Sandlie
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Peter
authors.initials: P
authors.lastname: Jebsen
authors.affiliation: Department of Biostatistics, Oslo University Hospital and University of Oslo, Faculty of Dentistry, Oslo, Norway.
authors.forename: Leiv
authors.initials: L
authors.lastname: Sandvik
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Dag Andre
authors.initials: DA
authors.lastname: Nymoen
authors.affiliation: Departments of Laboratory Medicine, Medical Epidemiology & Biostatistics, Karolinska Institute and Department of Clinical Microbiology and Pathology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Davit
authors.initials: D
authors.lastname: Bzhalava
authors.affiliation: Departments of Laboratory Medicine, Medical Epidemiology & Biostatistics, Karolinska Institute and Department of Clinical Microbiology and Pathology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Dillner
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, Oslo University Hospital and University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
authors.forename: Kjell
authors.initials: K
authors.lastname: Brøndbo
mesh_terms: D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D007822:Laryngeal Neoplasms / Q000150:complications*; D009664:Norway / Q000453:epidemiology; D010212:Papilloma / Q000150:complications* / Q000821:virology*; D027383:Papillomaviridae / Q000235:genetics*; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000150:complications / Q000821:virology*