MDM2 and CDK4 Immunohistochemistry: Should It Be Used in Problematic Differentiated Lipomatous Tumors?: A New Perspective

Although most cases of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) can be diagnosed solely on the basis of histologic features, those lacking diagnostic histologic features require ancillary studies for accurate classification. Fluorescent in situ hybridization (FISH) for amplification of MDM2 has been considered the gold standard for diagnosis in these situations. Immunostaining for MDM2 and/or CDK4 has been adopted as a surrogate method because of its high concordance rate with FISH and lower cost. However, studies examining the concordance of the 2 methods have been based preferentially on cases in which the diagnosis could be established histologically. No study has explored the concordance between the 2 methods in histologically ambiguous cases or in cases in which the diagnosis of ALT/WDL is not apparent after a review of all slides. To address this, we performed immunostaining for MDM2 and CDK4 on 183 well-differentiated lipomatous tumors that could not be diagnosed on purely histologic grounds and that were, therefore, subjected to FISH analysis. These included ALT/WDLs (n=56), lipomas (n=96), and lipoma variants (n=31). Staining for MDM2 and CDK4 was noted in 25/56 and 23/56 ALT/WDL, respectively, giving a sensitivity of 45% and 41% and a specificity of 98% and 92%. Staining was noted exclusively in the nuclei of atypical cells and not in the nuclei of adipocytes. Staining for MDM2 and CDK4 occurred in 2/125 and 10/117 benign lipomatous lesions, respectively. False-positive staining was equivalent in intensity to ALT/WDL. We conclude that MDM2 and CDK4 staining is a relatively insensitive method for diagnosing ALT/WDL in cases that are histologically ambiguous, as staining is restricted to neoplastic cells with atypia that are underrepresented in these cases. Therefore, in cases like ours that closely simulate clinical practice, FISH is the more reliable and cost-effective option.