Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver−Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.

Algarve Biomedical Center Research Institute 8005 139 Faro Portugal

Bioptic Laboratory Ltd 305 99 Plzen Czech Republic

Coordinator of the International Head and Neck Scientific Group 35122 Padua Italy

Department of Hematology and Medical Oncology The Winship Cancer Institute Emory University Atlanta GA 30322 USA

Department of Oncology Section Head and Neck Oncology KU Leuven 3000 Leuven Belgium

Department of Otorhinolaryngology Head and Neck Surgery Hospital Universitario Donostia Biodonostia Research Institute University of Deusto 20014 San Sebastian Spain

Department of Otorhinolaryngology Jena University Hospital 07747 Jena Germany

Department of Pathology Copenhagen University Hospital 2100 Copenhagen Denmark

Department of Pathology Faculty of Medicine Charles University 301 66 Plzen Czech Republic

Faculty of Medicine and Biomedical Sciences University of Algarve 8005 139 Faro Portugal

Northern Lincolnshire and Goole NHS Foundation Trust Lincoln 999039 UK

Otorhinolaryngology Head and Neck Surgery University Hospitals Leuven 3000 Leuven Belgium

Sahlgrenska Center for Cancer Research Department of Pathology University of Gothenburg SE 405 30 Gothenburg Sweden

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Molecular pathology in diagnosis and prognostication of head and neck tumors