[Clinicopathological and molecular characteristics of extraskeletal myxoid chondrosarcoma: an analysis of sixteen cases].

Objective: To investigate the clinicopathological features, molecular characteristics and differential diagnosis of extraskeletal myxoid chondrosarcoma (EMC). Methods: A total of 16 cases of EMC diagnosed from January 2016 to February 2025 were collected from Luoyang Orthopedic-Traumatological Hospital of Henan Province (Henan Provincial Orthopedic Hospital, 3 cases) and Beijing Jishuitan Hospital, Capital Medical University (13 cases) for clinicopathological, immunohistochemical, fluorescence in situ hybridization (FISH) and next generation sequencing analyses and follow-up. Results: There were 11 males and 5 females, with a median age of 51(30, 73) years. The tumor sites included extremities (n=12), trunk (n=3), and sacrum (n=1). Histologically, EMC showed two distinct subtypes. Fourteen cases (14/16) were classic subtype with pale-blue myxoid or chondromyxoid matrix. The cells characteristically interconnected with one another to form cords, small clusters, and complex trabecular or cribriform patterns. The tumor cells were round, ovoid, short spindle or star-shaped; some may be rhabdoid with eosinophilic cytoplasm and eccentrically placed nuclei. Two cases were cellular subtype, demonstrating solid sheets of epithelioid cells with minimal intervening myxoid matrix, large vesicular nuclei, prominent nucleoli, and brisk mitotic activity. Immunohistochemistry showed that the cells diffusely or partially expressed vimentin, CD117, Syn, INSM-1, CD34, SMA and NSE, but were negative for pan-keratin (AE1/AE3), S-100, calponin, desmin and brachyury. INI1 expression was not deleted. The proliferation index of Ki-67 ranged from 2% to 15% in the classic subtype and 5% in the cellular subtype. NR4A3 gene rearrangement was detected by FISH in 15 cases (15/16), and EWSR1::NR4A3 fusion was confirmed by next-generation sequencing in 4 cases. Follow-up data were available in 14 patients (1-104 months), of whom 7 (7/14) developed local recurrence and 2 (2/14) developed distant metastases. Conclusions: EMC is a rare mesenchymal malignancy that arises not only in soft tissues but also in bone. The predominant histological subtype is classical EMC, with a minority presenting as cell-rich EMC. FISH detection of NR4A3 gene rearrangements provides a crucial value for the diagnosis. It needs to be differentiated from myoepithelial tumors, chordomas and myxoid liposarcomas.