Aberrant PLAG1 expression in pleomorphic adenomas of the salivary gland: a molecular genetic and immunohistochemical study

Abstract

The morphologic distinction of pleomorphic adenoma from other benign or low-grade salivary gland tumors is sometimes difficult and problematic because of their potentially overlapping histological patterns. A subset of pleomorphic adenoma harbors specific gene alterations involving PLAG1 or HMGA2, and the detection of these fusion genes and their products using formalin-fixed, paraffin-embedded (FFPE) tumor specimens may be a useful diagnostic adjunct. In the present study, gene fusions involving PLAG1 or HMGA2 were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis, with FFPE tumor tissues and immunohistochemical expression of PLAG1 in 45 pleomorphic adenomas, using a commercially available antibody. RT-PCR analyses identified the CTNNB1-PLAG1, LIFR-PLAG1, CHCHD7-PLAG1, and HMGA2-WIF1 fusion transcripts in eight, two, one, and one case, respectively. The TCEA1-PLAG1, HMGA2-FHIT, and HMGA2-NFIB fusion transcripts were not detected. Immunohistochemically, tumor cells in all 45 pleomorphic adenomas were positive for PLAG1, irrespective of PLAG1 rearrangements, even in the case with the HMGA2-WIF1 fusion transcript. Tumor cells displaying myoepithelial or cartilaginous differentiation were almost constantly positive for PLAG1, whereas a limited expression was observed in glandular or keratinizing cells. Among the 46 tumors other than pleomorphic adenoma, 4 carcinomatous components of carcinomas ex pleomorphic adenoma were positive for PLAG1, the other 39 were negative for PLAG1, and the remaining 3 were only faintly and/or focally stained, indicating that the immunohistochemical detection of PLAG1 is diagnostically useful. The present results also suggest that overexpression of PLAG1 is essential for the tumorigenesis of pleomorphic adenomas, although the mechanisms mediating PLAG1 overexpression seem to be variable.

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

“…2b), but is negative in myoepitheliomas lacking ductal differentiation [16]. Similarly, the majority of salivary pleomorphic adenomas are positive for PLAG1 [17,18] and frequent positivity is observed in 77 % of carcinomas ex pleomorphic adenoma in salivary gland, including those classified as the myoepithelial carcinoma subtype [19].…”

Morphology in Conjunction with Immunohistochemistry is Sufficient for the Diagnosis of Mammary Analogue Secretory Carcinoma

“…There are a handful of salivary gland tumors that have been demonstrated to have recurring cytogenetic abnormalities including adenoid cystic carcinomas [t(6;9) (MYB-NFIB)] [8][9][10], mucoepidermoid carcinomas [t(11:19) (MECT1-MAML2)] [11,12], pleomorphic adenomas (PLAG1 and HMGA2 rearrangements) [13][14][15][16][17], and hyalinizing clear cell carcinoma [t(12;22) (EWSR1-ATF)] [18,19]. In the majority of these tumors, the morphology is distinctive enough to allow for a diagnosis and molecular confirmation is typically not necessary.…”

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

“…The pathogenic role of PLAG1, however, appears to span all PA, including tumors without cytogenetic evidence of PLAG1 alteration and those with HMGA2 rearrangement. This conclusion is drawn from immunohistochemical and Northern blot studies showing PLAG1 overexpression in nearly all PA, regardless of PLAG1 status [11][12][13].…”

“…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].…”