MDM2 and CDK4 Coexpression and Coamplification Identifies among High-Grade Osteosarcomas a Distinct Subset Transformed from Low-Grade Osteosarcoma.
Akihiko Yoshida, Tetsuo Ushiku, Toru Motoi, Masashi Fukayama, Hitoshi Tsuda, Tatsuhiro Shibata. National Cancer Center, Tokyo, Japan; University of Tokyo, Japan; Teikyo University, Tokyo, Japan
Background: Low-grade osteosarcomas (LGOSs), namely, parosteal osteosarcoma and low-grade central osteosarcoma, are characterized by amplification of MDM2 and CDK4, which results in overexpression of the encoded proteins. LGOSs may occasionally transform to higher grade sarcomas (“dedifferentiation”), which often take the form of high-grade osteosarcomas. Interestingly, previous studies have reported MDM2 and CDK4 amplification and/or overexpression in a minority (5-10%) of “conventional” high-grade osteosarcomas. We hypothesized that a high-grade osteosarcoma with MDM2/CDK4 amplification and/or overexpression may actually represent a transformed osteosarcoma whose precursor low-grade component is unrecognized.
Design: Eighty-one consecutive untreated biopsy samples coded “high-grade osteosarcoma of the bone” were immunostained with antibodies for MDM2 and CDK4. Sixteen selected cases were also studied by quantitative real-time PCR for gene amplification status. Corresponding surgical resection materials of all the biopsy cases were subsequently reviewed to find out if low-grade osteosarcomatous component coexisted.
Results: Five (6%) cases showed coexpression of MDM2 and CDK4, and 2 of the 3 successfully studied cases harbored gene coamplification. Histological review of the resectates revealed low-grade component in 4 cases (80%), and the only tumor lacking the low-grade element showed focal weak immunoreactivity and no gene amplification. Of the remaining 76 cases, 5 (6%) were immunoreactive to either MDM2 or CDK4 alone, and 71 (88%) were negative for both MDM2 and CDK4. No gene amplification was detected in the 5 successfully studied cases lacking MDM2 and CDK4 coexpression; informative resection materials available for 57 cases revealed no coexisting low-grade component.
Conclusions: High-grade osteosarcomas rarely show MDM2 and CDK4 coexpression, and most positive cases, particularly when associated with gene amplification, correspond to those transformed from precursor low-grade osteosarcoma. Immunostaining may thus be useful in identifying a distinct subset of osteosarcoma, and contribute to the precise subclassification of this malignancy.
Category: Bone & Soft Tissue
Tuesday, March 1, 2011 1:00 PM
Platform Session: Section E, Tuesday Afternoon