PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry

Abstract

Pleomorphic adenoma is the most common benign tumor of the salivary glands. It has marked histological diversity with epithelial, myoepithelial and mesenchymal-type cells arranged in a variety of architectural and differentiation patterns. Pleomorphic adenoma gene 1 (PLAG1), shown to be consistently rearranged in pleomorphic adenomas, is activated by chromosomal translocations involving 8q12, the chromosome region that is most frequently affected in these tumors. In this study, we evaluated PLAG1 involvement in salivary gland tumorigenesis by determining the frequency of its alterations in a selected group of 20 salivary gland tumors: 16 pleomorphic adenomas and four carcinomas ex-pleomorphic adenoma, having in common the presence of karyotypic chromosome 8 deviations, either structural, with 8q12 rearrangements, or numerical, with gain of chromosome 8. PLAG1 status was analyzed using in situ hybridization techniques, on metaphase cells, by fluorescence detection and/or interphase cells in paraffin sections, by chromogenic detection. Except for one pleomorphic adenoma case (5%) that lacked PLAG1 involvement, 17 tumors (85%), (14 pleomorphic adenomas and three carcinomas ex-pleomorphic adenoma) showed intragenic rearrangements of PLAG1 and the remaining two cases (10%), (one pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma), had chromosome trisomy 8 only. To further investigate the role of PLAG1 on pleomorphic adenomas tumorigenesis, as well as the putative morphogenesis mechanism, we attempted to identify the cell types (epithelial vs myoepithelial) carrying 8q12/PLAG1 abnormalities by a combined phenotypic/genotypic analysis in four cases (three pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma) characterized by 8q12 translocations and PLAG1 rearrangement. In these cases, both cells populations carried PLAG1 rearrangements. This finding further supports the pluripotent single-cell theory, which postulates that the tumor-initiated, modified myoepithelial cell, evolves into the varied somatic cell phenotypes present in pleomorphic adenoma, and reinforces the role of PLAG1 on the tumorigenesis of benign and malignant pleomorphic adenoma.

Heterogeneous genetic profiles in soft tissue myoepitheliomas

“…22 Among these, carcinoma ex pleomorphic adenomas may still demonstrate PLAG1 alterations. 23 Finally, although an exceedingly rare phenomenon, pleomorphic adenoma can metastasize and give rise to a so-called benign metastasizing pleomorphic adenoma. 24 However, none of the reported cases has metastasized to the soft tissues.…”

Myoepithelial Neoplasms of Soft Tissue: An Updated Review of the Clinicopathologic, Immunophenotypic, and Genetic Features

“…Mixed tumors show PLAG1 gene rearrangement in 37-72 % of cases [15,29], suggesting a genetic relationship to their salivary gland counterparts, as up to 88 % of salivary pleomorphic adenoma [30] and up to 63-75 % of carcinoma ex pleomorphic adenoma have PLAG1 gene alterations [19,30].…”

PLAG1 Alteration in Carcinoma Ex Pleomorphic Adenoma: Immunohistochemical and Fluorescence In Situ Hybridization Studies of 22 Cases

“…Few CA-ex-PA have been evaluated for PLAG1 status [11,12,[14][15][16]. Martins et al [15] found PLAG1 rearrangement in 3 cases and trisomy 8 without gene alteration in 1 case among 4 selected CA-ex-PA that were known to have karyotypic deviations of chromosome 8 [15].…”