Malignant peripheral nerve sheath tumor (MPNST) is a rare, high-grade soft tissue sarcoma that poses substantial diagnostic challenges. This tumor poses significant diagnostic challenges due to variable histologic patterns, limited neural marker expression, and overlap with the spectrum of other high-grade sarcomas. Its heterogeneous histologic patterns, limited expression of neural markers, and significant morphologic overlap with other high-grade sarcomas often complicate accurate identification. Diagnosis is challenging and often requires contributions from clinical findings, radiology, immunohistochemistry, and molecular diagnostics, necessitating a multidisciplinary team for diagnosis and management. MPNST is associated with a high rate of recurrence and metastasis; therefore, early detection and lifelong follow-up after treatment are essential. Here, we report a 39-year-old woman who was diagnosed with extraskeletal myxoid Chondrosarcoma (EMC) after excision of a left thigh mass. Two years afterward, she had locally extensive recurrence and FDG-avid mediastinal metastases. Advancing quality-assessment, comprising extensive histopathology and focused molecular investigations, reclassified the diagnosis as high-grade MPNST, based on CDKN2A deletion and the absence of NR4A32 rearrangement. This clarification changed the management, referring her to neoadjuvant chemotherapy, debulking surgery, and a subsequent plan of adjuvant therapy. This revised diagnosis prompted a change in therapeutic strategy, with initiation of neoadjuvant chemotherapy followed by surgical debulking and planned adjuvant therapy. Although she had an initial response, the patient developed widespread metastatic disease and died 8 months later. This case highlights the difficulties in diagnosing MPNST, the importance of interdisciplinary teamwork, and the need for close monitoring in patients with high-grade MPNST.