MDM2 amplification in malignant peripheral nerve sheath tumors correlates with p53 protein expression.
BACKGROUND
MDM2 is known to be abnormally upregulated in a variety of human neoplasms, secondary to gene amplification. Assessment of MDM2 amplification is most useful clinically for separating lipomas (nonamplified) from atypical lipomatous neoplasms or well-differentiated liposarcomas (amplified). MDM2 amplification occurs in approximately 7% of all human neoplasms. In this study, we sought to determine the utility of MDM2 amplification for the separation of benign (schwannomas) and malignant peripheral nerve sheath tumors (MPNSTs). The expression of p53 was correlated with MDM2 amplification because early studies have indicated that MDM2 is rarely amplified in MPNSTs that express p53.


OBJECTIVE
To determine the percentage of MPNSTs with MDM2 amplification and the specificity of MDM2 amplification for malignancy in nerve sheath tumors.


METHODS
Fifteen MPNSTs, 14 neurofibromas, and 15 schwannomas were obtained from the files of the Department of Pathology. These cases underwent fluorescent in situ hybridization analysis for the presence of MDM2 amplification. Assessments were also made for cellularity (low or high), percentage of cells staining positively for p53 and MDM2 protein, and percentage of cells staining with MIB-1.


RESULTS
Of 15 MPNSTs, 3 (20%) demonstrated amplification of the MDM2 gene. No neurofibromas or schwannomas demonstrated MDM2 amplification. All 3 MDM2 -amplified MPNSTs were positive for p53. Correlation of MDM2 amplification status and p53 immunoreactivity was statistically significant (P  =  .004).


CONCLUSIONS
The low frequency (20%) of MDM2 amplification in our series of MPNSTs demonstrates that MDM2 fluorescent in situ hybridization has limited diagnostic value for the separation of benign schwannomas and MPNSTs. Our study demonstrated a positive correlation (P  =  .004) between MDM2 amplification and p53 expression.
ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah, USA.
Michelle L
ML
Wallander
Sheryl
S
Tripp
Lester J
LJ
Layfield
D000974:Antibodies, Antinuclear / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D003937:Diagnosis, Differential; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation / Q000235:genetics; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D009442:Neurilemmoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D009455:Neurofibroma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C440408:MIB-1 antibody; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2