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While the overall risk of malignancy is relatively low, a distinct molecular sub-group harboring\n                      <jats:italic>HMGA2<\/jats:italic>\n                      alterations seems to show an increased risk of malignant progression to carcinoma ex pleomorphic adenoma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      This study investigates\n                      <jats:italic>MDM2<\/jats:italic>\n                      amplification in\n                      <jats:italic>HMGA2<\/jats:italic>\n                      -altered pleomorphic adenoma, atypical pleomorphic adenoma, and carcinoma ex pleomorphic adenoma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this multicenter, retrospective case series analysis, we examined 37 cases of\n                      <jats:italic>HMGA2<\/jats:italic>\n                      -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\n                      <jats:italic>MDM2<\/jats:italic>\n                      amplification using a stepped approach by immunohistochemistry and FISH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Collectively, an\n                      <jats:italic>MDM2<\/jats:italic>\n                      amplification was present in 27% of pleomorphic adenoma (4 of 15), compared to 78% of carcinoma ex pleomorphic adenoma (14 of 18) (\n                      <jats:italic>p-value\u2009=\u20090.003<\/jats:italic>\n                      ). In the group of pleomorphic adenomas with atypical features, an\n                      <jats:italic>MDM2<\/jats:italic>\n                      amplification was present in 50% of cases (2 of 4). These findings indicate an association between\n                      <jats:italic>MDM2<\/jats:italic>\n                      amplification and malignancy. Strikingly, a mixed control group of 12 benign and malignant\n                      <jats:italic>PLAG1<\/jats:italic>\n                      -altered neoplasms showed no immunohistochemical staining for MDM2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Immunohistochemical MDM2 expression, including\n                      <jats:italic>MDM2<\/jats:italic>\n                      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\n                      <jats:italic>HMGA2<\/jats:italic>\n                      -altered pleomorphic adenomas and integrate\n                      <jats:italic>MDM2<\/jats:italic>\n                      analysis into routine diagnostics to corroborate the cytonuclear atypia in these challenging cases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12105-025-01794-y","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T08:09:29Z","timestamp":1746691769000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recurrent MDM2 Amplification in the Spectrum of HMGA2-Altered Pleomorphic Adenoma, Atypical Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma"],"prefix":"10.1007","volume":"19","author":[{"given":"Kimberly S. 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Due to the retrospective design of the study informed consent was waived. Written informed consent was obtained from the patient described in the index case.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"For this type of study informed consent is not required.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"For this type of study consent for publication is not required.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"56"}}