FINAL DIAGNOSIS
CIC-rearranged sarcoma.
DISCUSSION
CIC-rearranged sarcoma, included in the 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone, is a high-grade round cell undifferentiated sarcoma defined by the presence of CIC-related gene fusions [1].
CIC-rearranged sarcomas occur in a wide age range, with a median age of 25 to 35 years. These tumors typically occur in the deep soft tissues of extremities or trunk and less commonly in the head and neck, retroperitoneum or pelvis. Approximately 10% of these tumors involve the visceral organs (e.g., kidney, gastrointestinal tract, or brain), while primary bone tumors are rare [1-2].
Grossly these tumors are usually large, circumscribed, white to tan, and fleshy masses, with frequent necrosis and hemorrhage. Histopathologically, CIC-rearranged sarcomas are composed of diffuse sheets of small round cells with mild to moderate nuclear pleomorphism, vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, often with clearing. The tumor often displays a lobular architecture delineated by fibrotic stroma. Stromal myxoid change and a minor component of spindle or epithelioid cells may be seen in a subset of cases. High brisk mitotic rate and geographic necrosis with perivascular preservation in necrotic areas are common. By far, the most common CIC rearrangement partner is DUX4, accounting for 95% of cases [3]. Rare cases of CIC sarcomas are associated with non-DUX4 partners, including FOXO4, LEUTX, NUTM1, or NUTM2A [4-7].
By immunohistochemistry, CIC-rearranged sarcomas often express CD99 (patchy), WT1 (90-95%), and ETV4 (95-100%) [8]. This pattern of staining is particularly useful given the potential for false negativity with RNA sequencing algorithms and FISH studies [9]. Sarcomas with CIC::NUTM1 fusions express NUT protein. CIC-rearranged sarcomas pursue an aggressive clinical course that is markedly worse than Ewing sarcoma. The 5-year overall survival is estimated at 17-43%, with an inferior response to the current Ewing sarcoma chemotherapy regimens [1,2].
In conclusion, CIC-rearranged sarcomas are newly described high-grade round cell poorly differentiated sarcomas, defined by CIC fusion with different gene partners, most commonly CIC::DUX4, that are characterized by an aggressive clinical course and low survival rate.
REFERENCES
Contributed by Pooria Khoshnoodi, MD, and Ivy John, MD