Inverted papilloma and sinonasal malignancies in Sweden

Abstract: Background: Sinonasal malignancies (SNMs) are rare and in Sweden they account for approximately 0,1% of all malignancies and 5% of all head and neck malignancies. Apart from sinonasal malignant melanoma (SNMM), their incidence has been reported to decrease since 1960 while the survival rates have remained rather stable during the same time-period. Sinonasal inverted papilloma (IP) is a benign tumour with a high risk of local recurrence and a potential to malignify. The true incidence of IP is not yet known. From hospital based studies, its incidence has been estimated to approximately 0.5/100000 person years. Previous studies have reported a malignant transformation of IP in 1–53%. However, it is unknown to what extent IPs are associated with squamous cell carcinoma (SCC) on a population basis. Also, the aetiology and prognostic factors for IP are mainly unknown. However, human papillomavirus (HPV) has previously been suggested as an aetiological factor by some authors. Moreover, p16INK4a (p16) overexpression, is often considered as a surrogate marker for high risk HPV in oropharyngeal carcinomas, but whether there is a correlation between p16 and HPV in IP and/or the prognosis of IP is uncertain. Similarly, a prognostic role of tumour infiltrating lymphocytes (TILs) has been observed in many head and neck tumours. However, their role in IP is sparsely investigated. Prognostic research on cell cycle related proteins such as oncoprotein 18, also called Stathmin, and epidermal growth factor receptor (EGFR) is relatively new regarding IP. In summary, IP is a rare tumour and relevant knowledge regarding factors affecting recurrence, malignant transformation and prognosis is still limited. Aims: The overall aim of this thesis was to investigate possible prognostic factors in IP, more specifically HPV, infiltration of TILs and expression of stathmin and EGFR. The aim was also to present epidemiological data on IP on a population basis and to describe how incidence and survival have changed for SNMs in the Swedish population. Results: In total 3221 patients diagnosed with primary SNMs were identified in the Swedish Cancer Registry (SCR) from 1960-2010. Their incidence decreased during the study-period except for SNMM and adenoid cystic cancer. More than 50 % of the malignancies involved the nasal cavity. The five-year relative survival was highest for adenoid cystic cancer followed by adenocarcinoma. SNMM and undifferentiated carcinoma had the poorest prognosis. In the SCR 814 patients with IP were identified. The incidence of IP increased from 1960 to 2010. Patients with IP had an overrepresentation of SCC when compared with the general population although this proportion was lower than previously reported. 8 Prognostic factors were analysed in tumours from 98 patients diagnosed with IP in Stockholm between 2000-2010. In total, 12.2% of the IPs were HPV positive and p16 overexpression was found in the only high-risk HPV positive tumour. Patients with HPV positive lesions were younger and tended to present with more dysplasia and to relapse less frequently. The tumours also had a higher proportion of EGFR expression compared to HPV negative tumours (91.7% and 52.3%, respectively). Stathmin was expressed by the tumours cells and not at all or weakly in the normal mucosa and more specimens with dysplasia were stathmin-positive than specimens without dysplasia (40.0% as compared to 12.6%). Stathmin positive IPs also tended to have earlier recurrences, although this difference was not statistically significant. No correlation was observed between TILs or EGFR and prognosis. Conclusions: While the overall incidence of SNM showed a slight decrease, the incidence of IP has increased and SCC is less common among patients with IP than previously reported. The results suggest that patients with HPV positive and HPV negative IPs may have different clinical characteristics, possibly indicating two different disease entities. Stathmin is consistently expressed in inverted papilloma but not in the normal mucosa and stathmin positivity seems to be associated with dysplasia and possibly also with recurrence. Stathmin might therefore even more than EGFR be considered a future therapeutic target.