As PLAG1 and HMGA2 rearrangements are the most common genetic events in pleomorphic adenomas, we sought to investigate if these abnormalities are also present in the skin/soft tissue ME lesions.
Specific chromosomal translocations are recognized in pleomorphic adenoma (with translocation involving PLGA1 or HMGA2 gene) and mucoepidermoid carcinoma (with MECT1-MAML2 gene fusion).
However, numerous molecular/genetic advances in the understanding of salivary gland neoplasms during the last decade have facilitated the development of many useful diagnostic markers, such as PLAG1 and HMGA2 immunohistochemistry for pleomorphic adenoma and ETV6 fluorescence in situ hybridization for secretory carcinoma.
Multiple fusion variants of PLAG1 and HMGA2 have been reported; currently, however, little is known regarding the clinicopathological impacts of these fusion types METHODS AND RESULTS: We examined the PLAG1- and HMGA2-related fusion status in 105 PAs and 11 cases of carcinoma ex PAs (CXPA) arising from salivary glands and lacrimal glands to elucidate their correlation to the clinicopathological factors.
On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (n = 18) or 3) HMGA2 alteration (n = 12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n = 14).
The results strongly suggest that pleomorphic adenomas are the only exception to the rule that entities of benign tumors with HMGIC rearrangements also have subtypes with HMGIY rearrangements.
We examined two soft tissue myoepitheliomas, whose paraffin blocks were available, for fusion gene transcripts involving PLAG1 or HMGA2 specific for pleomorphic adenoma by a reverse transcription-polymerase chain reaction assay, and no fusion transcripts were detected.
Thus far, there is little information on the genetic profiles of cutaneous mixed tumors, although specific genetic aberrations including fusion genes involving PLAG1 and HMGA2 have been demonstrated in pleomorphic adenomas.
To evaluate a possible genetic relationship between these soft tissue and salivary gland tumors, PLAG1 expression levels and the genomic status of PLAG1 and HMGA2 were investigated in five soft tissue myoepitheliomas and one pleomorphic adenoma.
These findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign PA.
A second gene, HMGA2, known to be upregulated in a subset of salivary gland pleomorphic adenomas, was overexpressed in only 1 case of AMT (1 of 16) and in none of the cases of EMT (0 of 9).
These findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign PA.
However, in the pleomorphic adenoma expressing the HMGA2/WIF1 fusion transcript, we observed re-expression of HMGA2 wild-type transcripts and very low levels of WIF1 expression.
We here analyzed the mutational status of the TP53 gene, genomic amplification of MDM2, CDK4 and HMGA2 rearrangement/amplification as well as protein expression of TP53 (p53), MDM2 and CDK4 in 51 de novo and ex pleomorphic adenoma SDCs.25 of 51 cases were found to carry TP53 mutations, associated with extreme positive immunohistochemical p53 staining levels in 13 cases.
HMGA2 expression is a highly specific (96.2%), but low-sensitivity (29.8%), marker for PA and CA ex-PA when compared with histological mimics, and is frequently associated with rearrangement of the HMGA2 locus.