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MDM2 Amplification in Atypical Lipomatous Tumor

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Atypical lipomatous tumor/Well-differentiated liposarcoma (ALT/WDL) shows giant marker and ring chromosomes which contain amplified sequences of 12q13-15 region. This site contains several genes, including MDM2, CDK4, GLI, SAS, and HMGA2. The co-amplification of MDM2 and CDK4 results in decreased apoptosis and increased cell proliferation (due to unblocking of the cell cycle at G1/S checkpoint).

MDM2 stands for Murine Double Minute clone 2 - an oncogene in double minutes of spontaneously transformed mouse fibroblasts. MDM2 is a nuclear phosphoprotein that interacts with and blocks p53 activity and inhibits apoptosis.

MDM2 amplification is seen in 7% of all human cancers and 33% to 37% of sarcomas. Tumors overexpressing MDM2 include ALT/WDL, de-differentiated liposarcoma, intimal sarcoma, and low-grade osteosarcomas (parosteal, intramedullary).

Immunoreactivity for MDM2 and CDK4 can be used to separate benign lipomatous tumors from ALN/WDL and pleomorphic soft tissue sarcomas from de-differentiated liposarcomas. However, immunohistochemistry has significant limitations. False-positive reaction may be seen in a small percentage of spindle cell lipomas and pleomorphic lipomas, in histiocytes within foci of fat necrosis, and in some cases of nonlipomatous sarcomas.

In contrast, MDM2 amplification by fluorescence in-situ hybridization is a highly sensitive and a specific marker for the diagnosis of ALN/WDL and de-differentiated liposarcomas and their distinction from lipomas and pleomorphic soft tissue sarcomas respectively.

MDM2 amplification by FISH is recommended for the evaluation of lipomatous tumors in the following situations: lipomatous tumors with borderline cytologic atypia, recurrent lipomas, large deep-seated lipomas (>15 cm), and retroperitoneal/intra-abdominal lipomatous tumors without atypia.

This FISH image shows MDM2 amplification (red) in a case of ALT/WDL. CEP12-SG (green) is a reference probe for the centromeric region of chromosome 12. Image courtesy of: Dr. Runjan Chetty, Professor, Dept. of Pathology, University of Toronto, Toronto, Ontario, Canada; used with permission.

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