The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rapidly increasing in recent decades and OPSCC is currently the 12th most common cancer worldwide. Currently in Finland, close to 200 new OPSCCs are diagnosed annually, whereas in the 1990s the annual number of diagnosed cases was approximately 50. The main driver behind this phenomenon is high-risk (HR) human papillomavirus (HPV) that currently comprises more than a half of new OPSCCs in numerous Western countries including Finland. HPV-positive OPSCC differs distinctly in genetic and pathophysiologic profiles from HPV-negative OPSCC. Both HPV-positive and HPV-negative OPSCC are typically diagnosed at an advanced stage and thus require multimodal treatment approaches that often impair quality of life. In addition, the accuracy to detect HPV in tumor samples has remained suboptimal in clinical practice. The recognition of early clinical signs and finding of reliable diagnostic tools are essential to achieve earlier and accurate diagnosis, respectively. In general, the prognosis of HPV-positive OPSCC patients is excellent and thus there is an initiative to de-escalate the management protocol to decrease the incidence of treatment-related side-effects. Instead, the prognosis of patients with HPV-negative OPSCC has remained poor regardless of improvements in treatment strategies. Hence, new prognostic markers are necessary to develop better and personalized treatment strategies to improve patient outcome and avoid a treatment-related reduction in quality of life. We aimed to compare different HPV-detection methods against the standard method i.e. p16 immunohistochemistry (IHC) to increase the accuracy of detecting active HPV from OPSCC samples. In addition, we wanted to better understand the clinical behavior and early signs and symptoms of HPV-positive and HPV-negative OPSCC. We also studied the role of other oncoviruses (Epstein-Barr virus [EBV] and polyomaviruses) in OPSCC and potential prognostic markers including tumor volume, matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1). In situ hybridization (ISH) for HR HPV E6/E7 mRNA was found to be a superior method to detect active HPV in OPSCC and thus should be considered as an additional method to p16 IHC. The accurate HPV diagnostics is especially essential when considering de-escalated treatment for HPV-positive OPSCC patients. In our study cohort, HPV presented as the only virus that clearly stratified patients into two different disease entities by clinical behavior and prognosis. However, HPV may not be the only viral factor related to OPSCC. EBV, or more precisely EBV-encoded small RNA (EBER), was found to correlate significantly with HPV and the presence EBER was associated with poorer prognosis among HPV-negative patients. Tumor volume showed prognostic significance in both HPV-positive and HPV-negative OPSCC and was superior when compared with the most recent TNM classification. In addition, elevated TIMP-1 serum levels were significantly associated with poor prognosis in HPV-negative OPSCC patients. As a conclusion, both tumor volume and serum levels of TIMP-1 may serve as potential prognostic factors in OPSCC, especially for patients with HPV-negative tumors that typically have a poor prognosis.
|Tila||Julkaistu - 2019|
|OKM-julkaisutyyppi||G5 Tohtorinväitöskirja (artikkeli)|
LisätietojaM1 - 95 s. + liitteet
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