Abstract
CIC-rearranged sarcoma is a rare and aggressive undifferentiated round cell sarcoma that presents significant diagnostic challenges due to its histologic overlap with other round cell sarcomas. This review, conducted on behalf of the American Society of Dermatopathology Appropriate Use Criteria Committee (soft tissue subgroup), provides an overview of current immunohistochemical, cytogenetic, and molecular tests used to support the diagnosis of CIC-rearranged sarcoma. This comprehensive analysis included 36 studies, encompassing 436 CIC-rearranged sarcomas. The immunohistochemical markers, CD99 (typically non-diffuse), nuclear WT1, ETV4, and DUX4, were found to be relatively highly sensitive for CIC-rearranged sarcoma (CD99: 87%, WT1: 83%, ETV4: 85%, DUX4: 97%). However, the specificity of these markers is variable, with CD99 being highly non-specific, while WT1 (81%-90%), ETV4 (95%), and DUX4 (100%) offering greater specificity. CIC break-apart FISH can be a helpful and cost-effective assay for detection of CIC-rearrangements, but has a false-negative rate that ranges from 26% to 43%. Next-generation sequence RNA fusion analysis also carries a risk of false negatives, which may be partly mitigated through manual data review. Ultimately, an accurate diagnosis of CIC-rearranged sarcoma requires careful morphologic assessment in combination with immunohistochemical studies and cytogenetics/molecular assays.