Recurrent MDM2 Amplification in the Spectrum of HMGA2-Altered Pleomorphic Adenoma, Atypical Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma.

INTRODUCTION

Pleomorphic adenoma is the most common neoplasm of the salivary glands. While the overall risk of malignancy is relatively low, a distinct molecular sub-group harboring HMGA2 alterations seems to show an increased risk of malignant progression to carcinoma ex pleomorphic adenoma.

PURPOSE

This study investigates MDM2 amplification in HMGA2-altered pleomorphic adenoma, atypical pleomorphic adenoma, and carcinoma ex pleomorphic adenoma.

METHODS

In this multicenter, retrospective case series analysis, we examined 37 cases of HMGA2-altered pleomorphic adenoma, carcinoma ex pleomorphic adenoma, and pleomorphic adenoma with atypical features. A total of 18 cases were included from our institutional archives, with 19 additional cases derived from published literature. The cases from our institutes were analyzed for MDM2 amplification using a stepped approach by immunohistochemistry and FISH.

RESULTS

Collectively, an MDM2 amplification was present in 27% of pleomorphic adenoma (4 of 15), compared to 78% of carcinoma ex pleomorphic adenoma (14 of 18) (p-value = 0.003). In the group of pleomorphic adenomas with atypical features, an MDM2 amplification was present in 50% of cases (2 of 4). These findings indicate an association between MDM2 amplification and malignancy. Strikingly, a mixed control group of 12 benign and malignant PLAG1-altered neoplasms showed no immunohistochemical staining for MDM2.

CONCLUSION

Immunohistochemical MDM2 expression, including MDM2 amplification, is enriched in the group of HMGA2-altered pleomorphic adenoma, and potentially plays role in malignant progression. This study highlights the importance of recognizing the molecular sub-group of HMGA2-altered pleomorphic adenomas and integrate MDM2 analysis into routine diagnostics to corroborate the cytonuclear atypia in these challenging cases.