Page 63 - New epidemiological and PSMA-expression based paradigms in salivary gland tumors

Malignant transformation of pleomorphic adenoma: Proof of principle
Introduction
The risk of malignant transformation from the most common salivary gland tumor, pleomorphic adenoma (SGPA), to the 5th most frequent salivary gland carcinoma (carcinoma ex pleomorphic adenoma; CEPA), is notorious [1,2]. It can lead to dilemmas in both pathological diagnosis and surgical/adjuvant radiation treatment of primary and recurrent pleomorphic adenoma (RPA). This risk of malignant transformation is, however, rare as only 3% of SGPAs recur at 12.5 year follow-up, of which 6% seem to show malignant transformation [1].
The hypothesis that malignant transformation of SGPA occurs is mainly based on the recognition of a pleomorphic adenoma component in malignant salivary gland tumors that are therefore classified as “carcinoma ex pleomorphic adenoma”. In these tumors, morphological as well as molecular transitions are seen from the benign pleomorphic adenoma component to the malignant carcinoma component [3–13]. At the molecular level, the pleomorphic adenoma component is recognized by the presence of PLAG1 and HMGA2 gene fusions[6,7,14], while the malignant component harbours additional mutations such as TP53, c-MYC, RAS, and P21[8,15–19]. These events have been shown within CEPA as well as in studies comparing SGPA and CEPA cases but not in sequential lesions from one patient [8,15–18].
CEPA can be diagnosed as a primary malignant tumor or as a recurrence after a benign earlier resected SGPA [9,20,21]. In both cases, malignant transformation is thought to result from progression of a SGPA, due to accumulation of genetic changes. SGPA itself is characterized by PLAG1 gene overexpression frequently due to a chromosomal translocation resulting in a gene fusion with several candidate genes [10–12]. Progression to CEPA due to HMGIC and possibly MDM2 amplification has been suggested [3,13].
This report shows for the first time that malignant transformation is accompanied by the accumulation of mutations in tumor driver genes in sequentially occurring parotid tumors, by means of targeted next generation sequencing (NGS) including copy number variation detection analysis using single nucleotide polymorphisms (SNPs) on 12 chromosomes and RNA-based gene-fusion analysis.
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