129 Cutaneous High-Grade Malignant Peripheral Nerve Sheath Tumor with MDM2 Amplification and H3K27me3 Loss

Introduction/Objective Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that often arise in the setting of neurofibromatosis type 1 (NF1) or following radiation therapy. Distinguishing MPNSTs from other high-grade sarcomas, such as dedifferentiated liposarcoma (DDLPS), can be challenging due to overlapping histologic and immunohistochemical features. MDM2 amplification, a hallmark of DDLPS, has been reported in a subset of MPNSTs, complicating the diagnostic process. Additionally, loss of H3K27me3 expression, a marker associated with Polycomb Repressive Complex 2 (PRC2) dysfunction, has emerged as a sensitive but not entirely specific marker for MPNST. We present a case of a high-grade radiation-associated sarcoma with MDM2 amplification and H3K27me3 loss, highlighting the diagnostic complexities and the importance of integrating clinical, histologic, and molecular findings. Methods/Case Report A 68-year-old female with a history of left breast cancer treated with mastectomy, chemotherapy, and radiation in 2001 presented with a 9 x 6 cm left chest wall mass. Imaging revealed osseous destruction and pleural invasion, suggestive of malignancy. A biopsy showed a high-grade spindle cell sarcoma with intersecting fascicles, pleomorphic cells, brisk mitotic activity, and extensive necrosis. Immunohistochemistry revealed focal positivity for S100, panCK, desmin, and complete loss of nuclear H3K27me3 expression. The tumor was negative for SOX10, INSM1, and other markers. Fluorescence in situ hybridization (FISH) demonstrated MDM2 amplification. Despite the MDM2 amplification, the overall clinical history, morphology, and immunohistochemical profile supported a diagnosis of high-grade MPNST, likely radiation-associated. Results NA Conclusion This case illustrates the diagnostic challenges in distinguishing MPNST from other high-grade sarcomas, particularly in the setting of radiation-associated tumors. MDM2 amplification, typically associated with DDLPS, has been reported in up to 20% of MPNSTs, as seen in our case. The loss of H3K27me3 expression, while highly suggestive of MPNST, is not entirely specific, as it has also been reported in a small subset of DDLPSs with PRC2 mutations. The presence of both MDM2 amplification and H3K27me3 loss in this case underscores the importance of integrating clinical context, histologic features, and molecular findings. While MDM2 amplification may raise the possibility of DDLPS, the absence of lipogenic differentiation, focal S100 positivity, and radiation history favor MPNST.