CIC-rearranged sarcoma is high-grade round cell sarcoma characterized by CIC gene rearrangement, most commonly CIC::DUX4. 

CIC-rearranged sarcoma occurs over a wide age range, with a predilection for young adults and a slight male predominance.¹ Although rare, CIC-rearranged sarcoma is the most common tumor among formerly unclassified, so-called "Ewing-like" sarcomas.²

Patients with CIC-rearranged sarcoma usually present with a palpable mass that can be painful. Up to 50% of patients present with metastatic disease that accounts for their symptoms.¹ About 85% of CIC-rearranged sarcomas occur in soft tissue sites, with most of the remainder occurring in viscera; bone is an uncommon primary site.¹

CIC-rearranged sarcoma contains sheets of neoplastic cells, often in large lobules separated by thin fibrous septa. The neoplastic cells can have round cell morphology or, in about half of cases in which more cytoplasm is present, they exhibit epithelioid or spindled morphology.¹ Characteristically, CIC-rearranged sarcoma exhibits vesicular nuclei with prominent nucleoli, and the degree of spindling and nuclear variability would be unusual for Ewing sarcoma. Myxoid stroma is present in about 30% of cases.¹

CIC-rearranged sarcoma frequently expresses membranous CD99, although the extent is usually less than in Ewing sarcoma.² NKX2.2, which is positive is Ewing sarcoma, is negative in about 95% of cases.³ CIC-rearranged sarcoma expresses nuclear WT1 and ETV4 (Fig. 1) in about 90% of cases.^1,4 These markers are specific and useful within the differential diagnosis of round cell sarcomas ⁵. Nuclear DUX4 expression is a promising immunohistochemical marker.⁶

Figure 1. ETV4 and WT-1 are each positive in about 90% of CIC-rearranged sarcoma.

CIC-rearranged sarcoma has a worse prognosis than Ewing sarcoma, with a 5-year survival of 44% compared to 76% for Ewing sarcoma in an age- and tumor stage-matched patient population.¹ 70% of studied cases in a large series showed a poor pathologic response to Ewing sarcoma-based treatment regimens.¹

• The CIC::DUX4 gene fusion most often results from either cryptic t(4;19)(q35;q13) (Fig. 2) or, less frequently, from t(10;19)(q26;q13), the latter involving the DUX4 paralog DUX4. No significant clinical-pathologic differences have been reported between tumors harboring either translocation.¹ Both DUX4 and DUX4 genes contain a 3.3-kb tandem repeat sequence located in the sub-telomeric regions of the long arms of chromosomes 4 and 10, respectively.

• There are examples of fusion partners other than DUX4, including FOXO4,⁷ NUTM1,⁸ and NUTM2A,(28188754} and occasionally other still-uncharacterized partner genes.

• FISH analysis using CIC break apart probes can detect most CIC rearrangements, but some cases may be missed due to cryptic translocations.⁹

• CIC-rearranged sarcoma exhibits recurrent trisomy 8,¹⁰ MYC amplification,¹¹ and chromosome 1p loss; ¹² there are also rare but recurrent driving point mutations.¹²

Figure 2. t(4;19)(q35;q13) in a CIC-rearranged sarcoma.