From the DEPARTMENT OF CLINICAL NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden

Since human papilloma virus (HPV) in the mid 1980ies was first observed in squamous cell carcinoma of the head and neck, its role and impact, especially on oral and oropharyngeal cancer, have attracted extensive interest. The aim of this thesis was to investigate if the clinical impression of increased incidence of tonsillar cancer was true, and if HPV could be linked to this increase. Molecular evidence that HPV could exert its transforming capacity in tonsillar cancer was searched for as well as if the presence of HPV had prognostic value. The Swedish Cancer Register was used to assess the incidence rates of tonsillar cancer over time. There was a significant increase since the register started, especially pronounced the last 15 years and in men. Paraffin embedded diagnostic biopsies were analysed to estimate the prevalence of HPV in tonsillar cancer in Stockholm between 1970-2002. Two hundred and three cases could be examined and the HPV prevalence was found to have increased from 23 % in the 70ies to 68 % in 2000-2002. HPV was found to be a strong favorable prognostic factor and patients harbouring HPV positive tumors fared better. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 were analyzed and in most HPV-16 positive tumors, expression of E6 and E7 was ascertained. Survival for patients with tonsillar cancer was assessed in a nationwide setting to see if the increased prevalence of HPV had any impact. The Swedish Cancer Register was used to evaluate the relative survival in tonsillar cancer since 1960 and the Stockholm cohort was studied thoroughly to determine if the improved survival was due to diagnostic or therapeutic improvements. The relative survival has increased, both in men and women, and when analysing the Stockholm cohort this could not be explained by improved treatment or earlier diagnosis. It is feasable that the increased survival of tonsillar cancer the last decades is caused by and closely related to the increase in HPV related tonsillar cancer This thesis report a parallel and substantial increase in the incidence of tonsillar cancer and the prevalence of HPV in tonsillar cancer in Sweden. HPV positive cases express their oncogenes and patients with HPV positive tumors have a significantly better disease specific survival. Finally, survival in tonsillar cancer improved in all over Sweden the last 40 years. This should pave way for future trials when planning treatment and also be addressed when discussing vaccination. LIST OF PUBLICATIONS I. Hammarstedt, L. , Dahlstrand H. , Lindquist D. , Onelov L. , Ryott M. , Luo J., Dalianis T. , Ye W. , Munck-Wikland E. (2007). The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 127(9): 988-92. II. Hammarstedt, L*. , Lindquist, D*. , Dahlstrand, H. , Romanitan, M. , Dahlgren, L. O. , Joneberg, J., Creson, N. , Lindholm, J., Ye, W. , Dalianis, T. & MunckWikland, E. (2006). Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 119, 2620-3. III. Lindquist, D*. , Romanitan, M*. , Hammarstedt, L. , Näsman, A. , Dahlstrand, H. , Lindholm, J., Onelöv, L. , Ramqvist, T. , Ye, W. , Munck-Wikland, E. & Dalianis, T. (2007). Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7. Molecular Oncology 1(3), 350-355. IV. Hammarstedt L. , Lu Y. , Lindquist D. , Dahlstrand H. , Dalianis T. , MunckWikland E. , Ye W. (2008) Improved survival for tonsillar cancer patients in Sweden. Submitted * Shared first authorship