High-grade uterine endometrial stromal sarcoma harboring GLI1 and MDM2/CDK4 co-amplifications
GLI1 gene alterations including fusions and amplifications compromise a subset of malignant mesenchymal tumors exhibiting characteristic monomorphic nested morphology and frequent S100 positivity, which mimic glomus tumors or well differentiated neuroendocrine tumors. We report four high-grade uterine endometrial stromal sarcomas (ESS) harboring GLI1 and MDM2/CDK4 co-amplifications with a median age of 51.5 years (range 43 ~ 72 years). Histologically, tumors showed a heterogenous morphology, including ovoid to spindle cells, showing nested/nodular arrangement (4/4). Myxoid background was observed at least partially in 4 tumors with prominent capillary networks. Mitoses index was 2 to 20/10 HPF (median 9.5/10 HPF). Immunochemically, tumors showed diffuse staining of CD10 (3/4) with frequently positive CyclinD1(2/4 tested) and mostly negative S100 protein (3/4). Next-generationsequencing (NGS) studies revealed GLI1 and MDM2/CDK4 co-amplification in all cases (4/4) and GLI1 fusion in 1 case (1/4), which were validated by fluorescence in situ hybridization (FISH) analysis. BCOR fusions were firstly identified with GLI1 and MDM2/CDK4 co-amplification in 2 cases (2/4). Copy number (CN) segmentation data showed GLI1 co-amplified cases present generally a single peak at the 12q13.3-15 locus. Follow-up (range:3 to 112 months; median 37.5 months) showed recurrence and/or metastasis in all cases (4/4), in which 1 patient developed lungs and liver metastasis. Relapse-free survival (RFS) analysis showed similar median RFS between GLI1 co-amplified HGESS and GLI1 non-amplified HGESS groups, which were shorter than LGESS group. Unusual clinicopathologic features of these HGESS with GLI1 and MDM2/CDK4 co-amplification mimicked other neoplasms, which caused significant diagnostic challenge and pitfalls. However, identification of GLI1 alterations in these tumors is beneficial for diagnosis and potential use of targeted GLI1 inhibitors.
Journal
Diagnostic PathologyAuthors
Funding
Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Technology Dissemination and Optimization Management Program of Shanghai Shenkang Hospital Development Center Grant SHDC22025202Clinical Research Program of Zhongshan Hospital, Fudan University Grant 2023ZSLC63Clinical Research Program of Zhongshan Hospital, Fudan University Grant 2023ZSLC63Clinical Research Program of Zhongshan Hospital, Fudan University Grant 2023ZSLC63Science and Technology Innovation Fund of Zhongshan Hospital, Fudan University Grant 2024ZSCX08Science and Technology Innovation Fund of Zhongshan Hospital, Fudan University Grant 2024ZSCX08Science and Technology Innovation Fund of Zhongshan Hospital, Fudan University Grant 2024ZSCX08National Natural Science Foundation of China Grant 32571067