Extraskeletal Osteosarcoma: MDM2 and H3K27me3 analysis of 19 cases suggest disease heterogeneity

Abstract

Aims

Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. Dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumor (MPNST) are the two most common types of sarcoma that can harbor heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST.

Methods and results

We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, 2 of which contained a low-grade component. The ESOSs affected deep soft tissues (n=10), superficial soft tissues (n=3), and organs (n=6). Among 10 deep soft-tissue ESOSs, 6 showed MDM2 amplification, 4 of which also harbored CDK4 co-amplification. Both ESOSs with a low-grade component showed co-amplification for MDM2 and CDK4. Among the 6 organ-based ESOSs, 3 giant cell-rich ESOSs showed an H3K27me3 deficiency (1 in primary and 2 in metastatic sites). Using targeted next generation sequencing, an H3K27me3-deficient ESOS showed EED homozygous deletion, while none of the 3 showed alterations in NF1, CDKN2A, or SUZ12 genes. During median follow-up of 20 months, all 6 patients with MDM2-amplified ESOS lived for 3–103 months, while 2 of the 3 patients with H3K27me3-deficient ESOS died from this disease in 4 and 20 months, respectively.

Conclusion

We demonstrate that ESOS may include at least two small subsets: an MDM2-amplified deep soft-tissue ESOS (which may be related to DDLPS) and an H3K27me3-deficient organ-based ESOS (which is probably unrelated to MPNST). Larger studies are required to validate the present observations and investigate the clinical implications of such subcategorization.

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