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Ameloblastoma is a mostly benign, but locally invasive odontogenic tumor eliciting frequent relapses and significant morbidity. Recently, mutually exclusive mutations in BRAF and SMO were identified causing constitutive activation of MAPK and hedgehog signaling pathways. To explore further such clinically relevant genotype-phenotype correlations, we here comprehensively analyzed a large series of ameloblastomas (98 paraffin block of 76 patients) with respect to genomic alterations, clinical presentation, and histological features collected from the archives of three different pathology centers in France, Germany, and Turkey. In good agreement with previously published data, we observed BRAF mutations almost exclusively in mandibular tumors, SMO mutations predominantly in maxillary tumors, and single mutations in EGFR, KRAS, and NRAS. KRAS, NRAS, PIK3CA, PTEN, CDKN2A, FGFR, and CTNNB1 mutations co-occurred in the background of either BRAF or SMO mutations. Strikingly, multiple mutations were exclusively observed in European patients, in solid ameloblastomas and were associated with a very high risk for recurrence. In contrast, tumors with a single BRAF mutation revealed a lower risk for relapse. We here establish a comprehensive landscape of mutations in the MAPK and hedgehog signaling pathways relating to clinical features of ameloblastoma. Our data suggest that ameloblastomas harboring single BRAF mutations are excellent candidates for neo-adjuvant therapies with combined BRAF/MEK inhibitors and that the risk of recurrence maybe stratified based on the mutational spectrum.

There are two major challenges in the early diagnosis of maxillary sinus carcinoma: the maxillary sinus is not susceptible to direct inspection and palpation, and symptoms are uncharacteristic. The aim of this study was to assess the impact of the time interval between first symptoms noticed by the patient and the detection of the tumor on survival. 88 patients with maxillary sinus tumors were included in the retrospective study. Prognostic factors were identified through univariate analysis. Univariate analysis (p = 0.019) revealed a significant impact of the time interval from first symptom to diagnosis on overall survival. With increasing duration of the symptoms 5-year overall survival was reduced from 65 % for duration between 0 and 2 months to 24 % for duration of symptoms longer than 12 months. Furthermore, we found a significant association (p = 0.033) between local extension of the tumor and time interval from first symptom to diagnosis. Early diagnosis is often difficult because of uncharacteristic symptoms, which are identical with benign diseases of the maxillary sinus. The delay between the occurrence of the first symptom and diagnosis often makes a curative treatment impossible.