Expanding the Molecular Spectrum of Carcinoma Ex Pleomorphic Adenoma

Abstract

Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive epithelial and/or myoepithelial neoplasm that arises in association with a pleomorphic adenoma (PA). Its etiopathogenesis remains poorly understood, but it is believed that the development of this tumor is due to the accumulation of genetic, protein, metabolic, and epigenetic alterations in a PA. A retrospective review of the Salivary Gland Tumor Registry in Pilsen yielded 84 CXPA, namely 25/84 salivary duct carcinoma (SDC), 15/84 myoepithelial carcinoma (MC), 1/84 epithelial-myoepithelial carcinoma (EMC), and 1/84 adenoid cystic carcinoma (AdCC). All 84 CXPA cases were analyzed by next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH). Forty-three tumors originally diagnosed as CXPA (43/84, 51.2%) showed some molecular alteration. Fusion transcripts were identified in 12/16 (75%) CXPA, including LIFR::PLAG1, CTNNB1::PLAG1, FGFR1::PLAG1, and a novel fusion, HMGA2::LINC02389. Most of the fusions were confirmed by FISH using PLAG1 (6/11) and HMGA2 (1/1) gene break probes. Split signals indicating gene break were identified by FISH for PLAG1 (12/17), HMGA2 (3/4), EWSR1 (7/22), and MYB (2/7). Concerning pathogenic mutations, only CXPA with epithelial differentiation (SDC) presented these alterations, including HRAS mutation (2/4), TP53 (1/4), PTEN (1/4), and ATK1 (1/4). In addition, amplifications in ERBB2 (17/35), MDM2 (1/4), and EWSR1 (1/7) were detected. A novel finding was the discovery of an HMGA2::LINC02389 fusion in 1 patient with EMC ex-PA. The present results indicate that molecular profiling of CXPA with myoepithelial differentiation (MC) tends to reveal chromosomal fusion events, whereas CXPA with epithelial differentiation (SDC) tends to have a higher frequency of pathogenic mutations and gene amplifications.