HMGA2 expression in CIC-rearranged sarcoma and other small round/epithelioid cell tumours

CIC-rearranged sarcoma (CRS), a highly aggressive sarcoma, is characterized by CIC fusion, with DUX4 being the most common partner. CRS is among the most difficult tumours to diagnose. Besides its relatively nonspecific small round or epithelioid morphology, genetic analyses often fail to detect CIC rearrangements. Although several diagnostic markers for CRS, namely WT1, MUC5AC, ETV4 and DUX4, have been introduced, their accessibility and interpretability are limited. Prompted by previous RNA-seq studies, we investigated the diagnostic utility of HMGA2 immunohistochemistry.

HMGA2 immunohistochemistry was evaluated in institutional archival cases from 2000 to 2025. Nine CRS and 119 other small round/epithelioid cell tumours were included. GATA3 and FOSL1 were also tested in selected CRS cases.

HMGA2 was frequently positive for CRS, with a sensitivity of 78% (strong expression) or 100% (any expression). It was positive in other small round epithelioid cell tumours, including a subset of Ewing sarcoma, EWSR1::NFATC2 sarcoma, sclerosing epithelioid fibrosarcoma, mesenchymal tumours with ACTB::GLI1 fusion, and malignant melanoma. Overall, the specificity was 82% (strong expression) and 70% (any expression). HMGA2 was more readily interpretable than WT1 and MUC5AC, and double-negative CRS cases were strongly positive for HMGA2. Three cases were negative for GATA3 and FOSL1.

HMGA2 may be more readily implemented than ETV4 and DUX4, even in non-specialized hospitals. Thus, HMGA2 immunohistochemistry is a useful adjunct for CRS diagnosis. HMGA2 expression in CRS and other small round or epithelioid cell tumours should be tested in a larger series, particularly in non-DUX4 CRS and ATXN1/ATXN1L-rearranged sarcomas.