MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone

Abstract

Low-grade osteosarcoma is a rare malignancy that may be subdivided into two main subgroups on the basis of location in relation to the bone cortex, that is, parosteal osteosarcoma and low-grade central osteosarcoma. Their histological appearance is quite similar and characterized by spindle cell stroma with low-to-moderate cellularity and well-differentiated anastomosing bone trabeculae. Low-grade osteosarcomas have a simple genetic profile with supernumerary ring chromosomes comprising amplification of chromosome 12q13-15, including the cyclindependent kinase 4 (CDK4) and murine double-minute type 2 (MDM2) gene region. Low-grade osteosarcoma can be confused with fibrous and fibro-osseous lesions such as fibromatosis and fibrous dysplasia on radiological and histological findings. We investigated MDM2-CDK4 immunohistochemical expression in a series of 72 low-grade osteosarcomas and 107 fibrous or fibro-osseous lesions of the bone or paraosseous soft tissue. The MDM2-CDK4 amplification status of low-grade osteosarcoma was also evaluated by comparative genomic hybridization array in 18 cases, and the MDM2 amplification status was evaluated by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction in 31 cases of benign fibrous and fibro-osseous lesions. MDM2-CDK4 immunostaining and MDM2 amplification by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction were investigated in a control group of 23 cases of primary high-grade bone sarcoma, including 20 conventional high-grade osteosarcomas, two pleomorphic spindle cell sarcomas/malignant fibrous histiocytomas and one leiomyosarcoma. The results showed that MDM2 and/or CDK4 immunoreactivity was present in 89% of lowgrade osteosarcoma specimens. All benign fibrous and fibro-osseous lesions and the tumors of the control group were negative for MDM2 and CDK4. These results were consistent with the MDM2 and CDK4 amplification results. In conclusion, immunohistochemical expression of MDM2 and CDK4 is specific and provides sensitive markers for the diagnosis of low-grade osteosarcomas, helping to differentiate them from benign fibrous and fibro-osseous lesions, particularly in cases with atypical radio-clinical presentation and/or limited biopsy samples.

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions

“…24 Although rare in jawbone locations, 25-27 diagnosis of low-grade osteosarcoma should be considered in the context of fibro-osseous lesions due to its specific management. 28,29 Overexpression and gene amplification of MDM2 in low-grade/dedifferentiated osteosarcomas, linked to supernumerary ring 12q13-15 chromosomes containing MDM2, 22,30 have together been proven to be a sensitive and specific diagnostic tool for these tumors in extragnathic locations. Unlike fibrous dysplasia and low-grade osteosarcoma, no recurrent genetic abnormalities have been reported for ossifying fibroma, which remains a lesion of uncertain nature, arising from the periodontal ligament.…”

“…[15][16][17][18] Cytogenetic abnormalities such as supernumerary ring chromosomes, including amplification of chromosome 12q13-15 leading to multiple copies of MDM2, characterize low-grade osteosarcoma. [19][20][21] To differentiate low-grade osteosarcoma from other fibro-osseous lesions, several studies have shown the diagnostic value of detecting overexpression of MDM2 by immunohistochemistry, 22,23 and MDM2 amplification by quantitative real-time PCR (qPCR), comparative genomic hybridization (CGH) array, or fluorescence in situ hybridization (FISH). 22 These studies mostly included cases of fibrous dysplasia and only a few cases of ossifying fibroma (six cases in Dujardin et al and none in Yoshida et al).…”

“…[19][20][21] To differentiate low-grade osteosarcoma from other fibro-osseous lesions, several studies have shown the diagnostic value of detecting overexpression of MDM2 by immunohistochemistry, 22,23 and MDM2 amplification by quantitative real-time PCR (qPCR), comparative genomic hybridization (CGH) array, or fluorescence in situ hybridization (FISH). 22 These studies mostly included cases of fibrous dysplasia and only a few cases of ossifying fibroma (six cases in Dujardin et al and none in Yoshida et al). No studies have specifically evaluated MDM2 status in craniofacial fibro-osseous lesions to date.…”

Osseous Dysplasia with Gross Jaw Expansion: A Review of 18 Lesions

“…Features which should raise the suspicion of an endosteal osteosarcoma include large areas of perforation of the cortical plates, infiltration of the surrounding soft tissue, failure to demonstrate maturation of the mineralized tissue into lobular bone masses and brisk mitotic activity [19]. MDM2 and CDK4 are sensitive markers for the diagnosis of low grade osteosarcomas [20] and may be helpful in differentiating the lace-like neoplastic osteoid from the cellular delicate osteoid and bone trabecula seen in expansive OD's. Trabecular juvenile ossifying fibromas are true neoplasms with an uncontrolled growth potential, affect younger patients and fail to demonstrate lobular maturation of mineralized tissue.…”

Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach

“…Osteosarcoma generally lack reactivity with other markers in the differential diagnostic considerations of a small round blue cell tumor, but MDM2, CDK4, and osteonectin may help in difficult cases. 95,96 Outcome and management. Osteosarcomas of the sinonasal tract must be resected with clear margins if a good outcome is to be expected, but difficult to achieve in this site, with chemotherapy frequently employed.…”