Evaluation of GNAS Mutations in Fibrous Dysplasia and Its Malignant Mimics, Including the Novel Finding of GNAS Mutation in Parosteal Osteosarcoma
Jodi M Carter, Long Jin, Barbara R Evers, Carrie Y Inwards, Andre M Oliveira, Karen J Fritchie. Mayo Clinic, Rochester, MN
Background: Fibrous dysplasia is a benign fibro-osseous disorder that shares morphologic features with several benign and malignant primary bone neoplasms. While the diagnosis of fibrous dysplasia may be straightforward when adequate sampling is coupled with radiologic correlation, pathologists are often asked to evaluate small biopsy specimens. Mutations in GNAS, the gene encoding the stimulatory alpha subunit of the heterotrimeric G protein complex, are commonly found in fibrous dysplasia, but very few studies have evaluated GNAS mutational status in malignant bone-forming tumors that may simulate fibrous dysplasia. We sought to evaluate the role of GNAS mutational analysis as an ancillary technique in distinguishing fibrous dysplasia from its benign and malignant histologic mimics.
Design: Cases of monostotic fibrous dysplasia (N=12), adamantinoma (N=3), osteofibrous dysplasia (N=4), parosteal osteosarcoma (N=7) and low grade central osteosarcoma (N=1) were retrieved from our institutional archives. Clinical, radiologic and histologic features were re-evaluated to confirm the previous diagnoses. DNA was extracted from paraffin-embedded tissues, and GNAS exons 8 (region containing codon 201) and 9 (region containing codon 227) were evaluated by PCR and direct sequencing.
Results: Ten cases of fibrous dysplasia harbored GNAS mutations in codon 201 (exon 8), including R201H (5 cases) and R201C (5 cases), while two cases had wild type GNAS. Four (of 7) parosteal osteosarcomas (humerus (N=2) and femur (N=2); 3 females and 1 male; age range 15-42 years old) and one low-grade central osteosarcoma (tibia, female, 29 years old) harbored GNAS R201C mutations. No GNAS codon 227 (exon 9) mutations were found. Three cases of parosteal osteosarcoma had wild type GNAS. No GNAS mutations were detected in cases of adamantinoma or osteofibrous dysplasia.
Conclusions: In our series, ten of twelve fibrous dysplasia cases had activating GNAS mutations, comparable to the reported rates in the literature. However, in our series of seven parosteal osteosarcomas, four cases had GNAS (R201C) mutations as did one case of low grade central osteosarcoma. To the best of our knowledge, this is the first report of GNAS mutations in parosteal osteosarcoma. Thus. while GNAS mutational analysis may help distinguish fibrous dysplasia from benign histologic mimics such as osteofibrous dysplasia and adamantinoma, it may be of limited utility in distinguishing fibrous dysplasia from low grade central and parosteal osteosarcoma.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 11:00 AM
Proffered Papers: Section G, Tuesday Morning