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Introduction <p>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 <i>HMGA2</i> alterations seems to show an increased risk of malignant progression to carcinoma ex pleomorphic adenoma.</p> Purpose <p>This study investigates <i>MDM2</i> amplification in <i>HMGA2</i>-altered pleomorphic adenoma, atypical pleomorphic adenoma, and carcinoma ex pleomorphic adenoma.</p> Methods <p>In this multicenter, retrospective case series analysis, we examined 37 cases of <i>HMGA2</i>-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 <i>MDM2</i> amplification using a stepped approach by immunohistochemistry and FISH.</p> Results <p>Collectively, an <i>MDM2</i> amplification was present in 27% of pleomorphic adenoma (4 of 15), compared to 78% of carcinoma ex pleomorphic adenoma (14 of 18) (<i>p-value = 0.003</i>). In the group of pleomorphic adenomas with atypical features, an <i>MDM2</i> amplification was present in 50% of cases (2 of 4). These findings indicate an association between <i>MDM2</i> amplification and malignancy. Strikingly, a mixed control group of 12 benign and malignant <i>PLAG1</i>-altered neoplasms showed no immunohistochemical staining for MDM2.</p> Conclusion <p>Immunohistochemical MDM2 expression, including <i>MDM2</i> 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 <i>HMGA2</i>-altered pleomorphic adenomas and integrate <i>MDM2</i> analysis into routine diagnostics to corroborate the cytonuclear atypia in these challenging cases.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • Kimberly S. T. Burghout,
  • G. E. Breimer,
  • S. Koppes,
  • H. M. Hazelbag,
  • M. L. Ooft,
  • G. M. Raicu,
  • A. M. Cleton-Jansen,
  • T. van Wezel,
  • R. van Eijk,
  • D. Terlouw,
  • S. L. van Egmond,
  • V. T.H.B.M. Smit,
  • N. J. Rupp,
  • D. Cohen

摘要

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.