Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics

Yoshida, Akihiko; Ushiku, Tetsuo; Motoi, Toru; Shibata, Tatsuhiro; Beppu, Yasuo; Fukayama, Masashi; Tsuda, Hitoshi

doi:10.1038/modpathol.2010.124

Cited by 160 publications

(102 citation statements)

References 32 publications

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“…The importance is highlighted by the knowledge that MDM2 amplification occurs in the majority of parosteal osteosarcomas and a small number of high-grade central osteosarcomas. [21][22][23][24] Nevertheless, the large numbers of soft-tissue sarcomas of various types studied here, and by others, 3,5,8 argues that MDM2 amplification is largely restricted to atypical lipomatous tumor and dedifferentiated liposarcoma in soft-tissue tumors. Indeed, only 8 of 201 (4%) non-lipomatous tumors were found to harbor MDM2 amplification with or without multiple faint alphoid 12 signals.…”

Section: Discussionmentioning

confidence: 52%

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Kashima

Halai

et al. 2012

Modern Pathology

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This study assessed whether analysis of MDM2 copy number by fluorescence in situ hybridization (FISH) would help distinguish lipomas from atypical lipomatous tumors, otherwise referred to as well-differentiated liposarcomas, using a commercially available MDM2 FISH kit. 227 lipomatous and 201 non-lipomatous tumors were analyzed to assess its sensitivity and specificity. Of 178 mature lipomatous tumors, 86 were classified histologically as lipoma and 92 as atypical lipomatous tumor. Two of the lipomas harboring MDM2 amplification were reclassified as atypical lipomatous tumors. Overall, 13 atypical lipomatous tumors did not reveal MDM2 or CDK4 amplification, although this was reduced to 12 following analysis of multiple slides. Three of these cases revealed very occasional tumor cells harboring high-level MDM2 amplification, two had a dedifferentiated component, and MDM2 amplification was detected when one tumor recurred. The remaining six cases exhibited reactive/inflammatory features and were reclassified as lipomas. The findings indicate that MDM2 amplification is 93.5% sensitive for diagnosing atypical lipomatous tumor. A total of 2 of the 20 dedifferentiated liposarcomas failed to reveal MDM2 amplification. All atypical lipomatous tumors measured 410 cm, two dedifferentiated liposarcoma presented de novo at o10 cm, and B50% of lipomas measured 410 cm. Spindle cell lipomas, lipoblastomas, hibernomas and pleomorphic liposarcomas did not reveal MDM2 amplification. Of 201 nonlipomatous tumors, eight revealed MDM2 amplification or multiple faint alphoid 12 signals and were reclassified as dedifferentiated liposarcoma. Multiple faint alphoid 12 signals were observed in nine tumors from seven patients, an observation not previously reported on paraffin sections: these included four atypical lipomatous tumors, and three dedifferentiated liposarcomas, one previously diagnosed as a myxofibrosarcoma, all of which also revealed amplification of CDK4, although two lacked MDM2 amplification. MDM2 FISH test is a useful adjunct to histology for distinguishing lipoma from atypical lipomatous tumor. The limitations of molecular genetic tests must be known before introducing them into a clinical service.

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Section: Discussionmentioning

confidence: 52%

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Kashima

Halai

et al. 2012

Modern Pathology

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“…61 Their results confirmed the very good sensitivity of the test (100%) and its specificity (97.5%). However, the number of cases studied was lower and the MDM2 and CDK4 amplification status was not investigated.…”

Section: Discussionmentioning

confidence: 62%

“…Although some studies have reported 12q amplification in conventional high-grade osteosarcomas, with a frequency ranging from 0 to 27%, 19,50,52-59 the majority have indicated that amplification of MDM2 and CDK4 is a typical feature of parosteal osteosarcoma and lowgrade central osteosarcoma. 16,17,19,21,47,52,60,61 One study showed a high level of CDK4 and MDM2 amplification in a series of nine osteosarcomas of the jaw, including five intermediate and high-grade osteosarcomas. 51 However, gnathic osteosarcomas have particular clinical and biological profiles that differ from conventional high-grade osteosarcomas of long bones and that require further specific investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Low-grade osteosarcoma studies analyzing MDM2 expression by immunohistochemistry have reported a frequency range of 22-70 and 66-92% for CDK4. 20,21,[59][60][61] This wide range can be explained by technical differences, such as formalin fixation, decalcification of tissues, antibody dilution and antigen retrieval method. The biomolecular study of MDM2 amplification in low-grade osteosarcomas, including aCGH, FISH and PCR, has revealed a frequency range of 19-100 and 12-80% for CDK4.…”

Section: Discussionmentioning

confidence: 99%

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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

Dujardin

Binh²,

Bouvier³

et al. 2011

Modern Pathology

198

122

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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.

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“…[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).…”

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confidence: 99%

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

et al. 2015

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To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P ¼ 0.004), non-juvenile ossifying fibromas (P ¼ 0.001), and all other benign craniofacial fibro-osseous lesions combined (P ¼ 0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.

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Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics

Cited by 160 publications

References 32 publications

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

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

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

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