Gsα gene mutations in monostotic fibrous dysplasia of bone and fibrous dysplasia-like low-grade central osteosarcoma

K, Pollandt; Engels, C.C.; Kaiser, E.; Werner, Mathias; Delling, G.

doi:10.1007/s004280100453

Cited by 62 publications

(43 citation statements)

References 17 publications

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“…18,[35][36][37][38][39][40] Okada et al 41 studied eight cases of low-grade central osteosarcomas retrospectively and showed that proliferative cell activity evaluated by AgNOR and MIB-1 immunohistochemical staining was significantly higher in cases of low-grade central osteosarcoma than in fibrous dysplasia and might be helpful in differentiating low-grade central osteosarcoma from fibrous dysplasia. Pollandt et al 42 showed that Gsalpha gene mutations were a constant finding in cases of monostotic fibrous dysplasia. Nevertheless, they also reported a Gsalpha gene mutation in one of five cases of fibrous dysplasialike low-grade central osteosarcoma studied.…”

Section: Discussionmentioning

confidence: 99%

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

203

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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Section: Discussionmentioning

confidence: 99%

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

203

122

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“…Dedifferentiation affects 16-43% of parosteal osteosarcomas with the characteristic gene amplifications being retained and can be present at the first presentation (synchronous type) or at the time of recurrence (metachronous type). [7][8][9] Bone tumors analyzed previously for GNAS alterations include fibrous dysplasia (N = 405), [10][11][12][13][14][15][16] ossifying fibroma (N = 65), 10,12,[15][16] osteofibrous dysplasia (N = 19), 10,12-13 low-grade central osteosarcoma (N = 12) 10,13-14 , and parosteal osteosarcoma (N = 10). 10 GNAS mutations have been reported in fibrous dysplasia and have not been described until recently in any other fibrous osseous lesions with the exception of a single low-grade central osteosarcoma.…”

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confidence: 99%

“…10 GNAS mutations have been reported in fibrous dysplasia and have not been described until recently in any other fibrous osseous lesions with the exception of a single low-grade central osteosarcoma. 14 These reported GNAS mutations in fibrous dysplasia include p.R201C, 13 p.R201H, 13 p.R201S, 17 and p.Q227L. 13 A GNAS mutation in codon 201 (p.R201G) has been found in lesions in McCune-Albright syndrome.…”

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confidence: 99%

GNAS mutations are not detected in parosteal and low-grade central osteosarcomas

et al. 2015

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Parosteal osteosarcoma, low-grade central osteosarcoma, and fibrous dysplasia share similar histological features that may pose a diagnostic challenge. The detection of GNAS mutations in primary bone tumors has been useful in clinical practice for diagnosing fibrous dysplasia. However, the recent report of GNAS mutations being detected in a significant proportion of parosteal osteosarcoma challenges the specificity of this mutation. As the number of cases reported in this study was small we set out to determine if these results could be reproduced. We studied 97 formalin-fixed paraffin-embedded low-grade osteosarcomas from 90 patients including 62 parosteal osteosarcomas, of which MDM2 amplification was detected in 79%, 11 periosteal osteosarcomas and 24 low-grade central osteosarcoma samples. The mutational status of GNAS was analyzed in codons p.R201, p.Q227, and other less common GNAS alterations by bidirectional Sanger sequencing and/or next generation sequencing using the Life Technologies Ion Torrent platform. GNAS mutations were not detected in any of the low-grade osteosarcomas from which informative DNA was extracted. Our findings therefore support prior observations that GNAS mutations are highly specific for fibrous dysplasia and occur rarely, if ever, in parosteal and other low-grade osteosarcomas. Parosteal and low-grade central osteosarcomas are rare low-grade primary malignant bone tumors comprising o4% of all osteosarcomas. In contrast, fibrous dysplasia is one of the most common benign fibro-osseous tumor-like lesions in medullary bone. Morphologically, there is considerable overlap between these lesions all showing variably shaped bony trabeculae surrounded by spindled-shaped cells, with little to no cytologic atypia. 1 In the majority of cases, imaging studies can easily differentiate parosteal osteosarcoma from fibrous dysplasia and central low-grade osteosarcoma: parosteal osteosarcoma is a surface tumor that may secondarily invade bone marrow, and low-grade central osteosarcoma and fibrous dysplasia are centrally based. Occasionally, fibrous dysplasia arises eccentrically in the marrow space, presenting as an exophytic surfacebased lesion. Such lesions are referred to as fibrous dysplasia protuberans. 2 Hence, distinguishing fibrous dysplasia protuberans from parosteal osteosarcoma can be challenging and differentiating between lowgrade central osteosarcoma and fibrous dysplasia can also be difficult.Parosteal osteosarcoma typically harbors one or more supernumerary ring chromosomes with amplification of the MDM2, SAS, and CDK4 genes. 3,4 MDM2 amplification is reported to occur in 93% (14/15) of low-grade central osteosarcomas 3,5 and in 79% (68/86) of parosteal osteosarcomas. 5,6 Dedifferentiated parosteal osteosarcoma is a distinct tumor variant in which a (high-grade) sarcoma coexists with a conventional parosteal osteosarcoma. Dedifferentiation affects 16-43% of parosteal osteosarcomas

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“…In addition, this method may not be readily adoptable in the differential diagnosis of parosteal osteosarcoma and benign processes, because myositis ossificans and other benign surface lesions unfortunately tend to show some proliferative activity, and their increased labeling indices may overlap with those of sarcoma. Pollandt and co-workers, 28 on the other hand, took a molecular approach by performing Gsa gene mutation analysis to separate low-grade central osteosarcoma and fibrous dysplasia. They found that all nine fibrous dysplasias harbored this mutation, whereas such abnormality was not identified in four of five examples of fibrous dysplasialike low-grade central osteosarcoma.…”

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

et al. 2010

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Gsα gene mutations in monostotic fibrous dysplasia of bone and fibrous dysplasia-like low-grade central osteosarcoma

Cited by 62 publications

References 17 publications

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

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

GNAS mutations are not detected in parosteal and low-grade central osteosarcomas

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

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