The Utility of MDM2 and CDK4 Immunohistochemistry and MDM2 FISH in Craniofacial Osteosarcoma

Abstract

Craniofacial osteosarcoma is rare (2-10% of all osteosarcomas). Most low grade fibroblastic osteosarcomas of the long bones are characterized by amplification of chromosome12q including MDM2 and CDK4 genes. This study aims to investigate the utility of MDM2 and CDK4 immunostains as well as MDM2 FISH in craniofacial osteosarcomas as a means of distinguishing them from benign fibro-osseous lesions. Cases of primary osteosarcoma and benign fibro-osseous lesions of the craniofacial bones were identified in the diagnostic pathology archives. MDM2 (SMP14 and/or IF2) and CDK4 (D9G3E and/or DCS-31) immunostains were performed on a representative block from each osteosarcoma and benign case. Fluorescence in situ hybridization (FISH) for MDM2 was performed on non-decalcified osteosarcomas. In osteosarcomas, the rate of expression of either MDM2 IF2, MDM2 SMP14, CDK4 DCS-31, or CDK4 D9G3E was 72.7% (8/11 cases), usually focal and weak. Using the MDM2 IF2 clone and the CDK4 DCS-31 clone, MDM2 and CDK4 were negative in lesional cells in all 14 benign fibro-osseous lesions. Using the IF2 and SMP14 clones, MDM2 nuclear expression was present in associated osteoclast-like giant cells in both benign and malignant cases. Of 4 successful cases, 1 high grade osteosarcoma was positive for MDM2 amplification. MDM2 or CDK4 expression or MDM2 amplification may aid in a diagnosis of head and neck osteosarcoma. However, when absent, sarcoma is not excluded. Due to focal weak expression of MDM2 in tumor cells in conjunction with nuclear expression in associated giant cells, caution should be exercised when interpreting positive stains.

Professional diagnostic delay in osteosarcomas of the jaws

“…With regard to histopathologically differentiating OSJ from fibrous dysplasia and other benign fibrous and fibro-osseous lesions, immunohistochemical expression of murine double-minute type 2 MDM2) and cyclin-dependent kinase 4 (CDK4) may be helpful ( 10 ). However, when absent, osteosarcoma can not be excluded ( 11 ). In a study based on 61 OSs no immunohistochemical marker was found to be diagnostic of OS or its subtyping ( 12 ).…”

SATB2 and MDM2 Immunoexpression and Diagnostic Role in Primary Osteosarcomas of the Jaw

“…Our study found that 27% (3/11) of high-grade OSJs were positive for MDM2, while all BFOLs of the jaw and a Ewing sarcoma of the jaw were negative for MDM2. Other studies share similar results: a recent study by Lott Limbach et al showed that MDM2 was expressed in 63% (7/11) of craniofacial OSs and not expressed in any BFOLs of the jaw [ 32 ]. Meanwhile, Guerin et al showed that MDM2 was expressed in 8% (3/36) of craniofacial OSs, but they found no expression of MDM2 in any of the benign bone-forming tumors [ 21 ].…”

MDM2 Amplified Sarcomas: A Literature Review

“…In a high proportion of cases, immunohistochemical MDM2 and/or CDK4 expression can be found as well. In this respect, search for MDM2 amplification/expression can be very useful to distinguish these low-grade sarcomas from their—often benign—mimics ( Figure 11 and Figure 12 ) [ 44 ]. The prognosis of both neoplasms is excellent, with 5-year survival rates of 90% upon complete resection.…”