CIC-rearranged sarcoma is characterized by round cell undifferentiated histology, frequent expression of ETV4 and WT1, and aggressive behavior. A clinical encounter of a case with CIC-DUX4 fusion and ERG/CD31 co-expression prompted us to systematically investigate ERG and CD31 expression status in 30 archival cases of CIC-rearranged sarcoma. Half (15) of them showed moderate or strong ERG expression in <5–100% of tumor cells, among which nine showed heterogeneous membranous CD31 reactivity, including four cases each showing diffuse or strong expression. None of them showed uniformly strong and diffuse ERG/CD31 co-expression; however, three cases were initially interpreted and treated as angiosarcoma without response. Except for smaller superficial tumor enrichment, the clinicopathological characteristics of these nine cases of ERG+/CD31+ CIC-rearranged sarcoma did not differ from those of remaining 21 cases. Five showed focal hemorrhagic clefts/cysts, mimicking vascular spaces. All tumors expressed ETV4 and/or nuclear WT1, and fusion to DUX4 was confirmed in seven cases. Four tumors examined by next-generation sequencing harbored no CIC missense mutations. Using DNA methylation profiling, one CD31+ CIC-rearranged sarcoma was clustered with CD31− CIC-rearranged sarcomas, but distant from angiosarcomas. When compared with epithelioid angiosarcomas lacking CIC rearrangements, ERG+/CD31+ CIC-rearranged sarcomas were distinguished by focal myxoid change and the entire lack of vasoformative architecture. The angiosarcomas were characterized by uniform strong expression of ERG and CD31, but none of them were found positive for ETV4 or nuclear WT1. Heterogeneous ERG/CD31 co-expression in a subset of CIC-rearranged sarcoma is a clinically relevant pitfall for angiosarcoma, as these two diseases are treated differently.
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The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request and IRB approval.
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The authors thank Sachiko Miura, Toshiko Sakaguchi, Chizu Kina, Hiroki Kakishima, and Hiroshi Chigira for their superb technical assistance.
This work was supported in part by JSPS KAKENHI (Grant Number JP21K06919, A.Y.) and the National Cancer Center Rare Cancer Grant (Award Number G007, A.Y.).
The authors declare no competing interests.
This study was approved by the Institutional Review Board of the National Cancer Center Hospital, Tokyo, Japan (No.2014-089).
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Kojima, N., Arai, Y., Satomi, K. et al. Co-expression of ERG and CD31 in a subset of CIC-rearranged sarcoma: a potential diagnostic pitfall. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01078-8