Malignant melanoma and other malignancies of the nasal cavity and the paranasal sinuses in Sweden

Background: Malignancies emerging in the nasal cavityand the paranasal sinusesare rare and accounts for 5% of all head and neck malignancies and 0.1% of all malignancies in Sweden. The incidence of sinonasal malignancy (SNM), except sinonasal malignant melanoma (SNMM), has been reported to decrease since 1960 in Sweden. Despite similar improvement in the prognosis of other malignancies, treatment of SNM still yields a poor survival outcome. About 1–2% of all malignant melanomas originate from mucosal membranes in the genitourinary, digestive and the respiratory regions, whereas mucosal melanomasare most frequently located in the nasal cavity, followed by sites in paranasal sinusesin the head and neck region. The incidence of cutaneous malignant melanoma (CMM) continues to increase in many parts of the world, possibly due mainly to the effects of sun-related behaviour; however, the incidence of mucosal melanomassuch as vulvar and ano-rectal melanoma display a more complicated pattern with a stable or decreasing incidence rate. We now know that the incidence of SNMM is increasing in Sweden, as we have documented one of the largest consecutively studied SNMM groups in the world. Nevertheless, the underlying mechanism remains unclear. The treatment options for these patients have remained the same over the years; mainly radical surgeryfollowed by radiotherapy. Alternatively, recent molecular-targeted therapy has become available for sub-groups of patients with malignant melanomas. Such therapeutic advances stress the importance of investigating the aetiology and molecular characteristics of SNMM, which are not yet well. Aims: Given the rarity of SNM and SNMM, relevant knowledge is limited. Therefore, the overall aim of this thesis was to examine the clinical characteristics and features of SNMM and SNM and to determine the occurrence of molecular alterations. They include KIT, NRAS and BRAF mutation frequenciesand mutation frequencyof the TERT ( Telomerase Reverse Transcriptase) promotor gene in SNMM. Results: In the first project, we identified 3221 patients from the Swedish National Cancer Registry diagnosed with primary malignancies arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2011. The anatomical site, gender and age, incidence and survival were scrutinized. We found that the incidence of sinonasal malignancies decreased except for SNMM and adenoid cystic cancerduring the study period. More than 50% of these malignancies involved the nasal cavity. The five-year relative survivalwas highest for patients with adenoid cystic cancerfollowed by adenocarcinoma. Those with SNMM and undifferentiated carcinoma had the poorest prognosis. In the second project we identified 186 SNMM patients during the period 1960 through 2000 in Sweden from the National Swedish Cancer Registry (SCR). We investigated the incidence, gender, age, primary anatomical sites, geographic distribution, treatment and survival. In this population the incidence of SNMM increased during the study period. The incidence for females was higher than for males, and the incidence increased with age for both genders. We found that about 70% of the tumours were clinically described as amelanotic. Surgery was the most common primary treatment. The five-year diseasespecific survival rates were poor for both genders, but females had a better survival than males. The survival rate improved for both genders during the study period, regardless of therapeutic strategy. We conclude that the incidence of SNMM in Sweden increased significantly from 1960 through 2000 but not as rapidly as that of CMM. In the third project, we analysed 56 primary SNMMs, the largest number, as far as we know, for mutations in KIT (exons 11, 13 and 17), NRAS (exons 1 and 2) and BRAF (exon 15) identified by using direct sequencing. Twelve of the 56 (21%) tumours contained mutations in these oncogenes, 2 tumours harboured KIT mutations, another 2 harboured BRAF mutation and 8 had NRAS mutations. We found a higher frequency of mutations in tumours originating from the paranasal sinusescompared to tumours from the nasal cavity(p=0.027). In the fourth project we analysed 49 SNMM tumours for TERT promotor gene mutations, since former investigators found only a few driver mutations for these patients, who were never previously examined for this mutation. Recent studies of CMM have shown a high frequency (>70%) of driver mutations in this gene. TERT promoter mutations occur at a moderate frequency in SNMM. We suggest that SNMM tumours should be included in molecular characterization, since these alterations probably will be therapeutic targets in the near future. LIST OF PUBLICATIONS I. Elliot A, Jangard M, Marklund L, Dickman P, Hakansson N, HammarstedtNordenvall L and Stjarne P. Sinonasal malignancies in Sweden 1960-2010; a nationwide study of the Swedish population. Accepted for publication in RhinologyII. Jangard M, Hansson J, and Ragnarsson-Olding B. Primary sinonasal malignant melanoma: a nationwide study of the Swedish population, 1960-2000. Rhinology, 2013. 51(1): p. 22-30. III. Zebary A*, Jangard*, Omholt K, Ragnarsson-Olding B, and Hansson J. KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases. Br J Cancer. 2013 Aug 6; 109:559-64. IV. Jangard M*, Zebary A*, Ragnarsson-Olding B, and Hansson J. TERT promotor gene mutation in sinonasal mucosal melanoma. Submitted for publication *These authors contributed equally