GLI1-Altered Mesenchymal Tumor-Multiomic Characterization of a Case Series and Patient-Level Meta-analysis of One Hundred Sixty-Seven Cases for Risk Stratification

GLI1-altered mesenchymal tumors have recently emerged as a distinctive group of neoplasms characterized by GLI1 fusions or amplifications. Although there is clearly metastatic potential, the clinicopathologic features predicting for metastasis are currently unknown. Herein, we present 6 cases of GLI1-altered mesenchymal tumors with multiomics analysis. The median patient age was 50 years (range, 3-68 years). They arose from the extremities and trunk (2/6), head and neck region (2/6), and gastrointestinal tract (2/6). Histologically, they featured uniform round to ovoid cells with nested architecture and a rich vascular network. One case displayed abundant multinucleated giant cells. All stained positive for GLI1 (5/5) and CD56 (6/6). Molecularly, they featured GLI1 fusion (5/6) and amplification (1/6). Fusion partners included ACTB (3/5), TXNIP (1/5), and novel TUBA1B (1/5). Multiomics analysis revealed they possessed distinct expression and epigenomic profiles. All the 6 cases had follow-up information, with 5 of them having no evidence of disease at a median follow-up of 30 months (range, 17.3-102 months), and 1 case being died of disease with regional neck lymph node and bilateral lung metastasis at 81.5 months of follow-up. By incorporating cases reported in the literature, we analyzed clinicopathologic features of a total of 167 cases predictive of malignant behavior. We found that size ≥6 cm and mitotic count ≥5 per 10 high-power fields are predictive of metastasis. Cases with both high-risk features had significantly poorer survival. This study expands the literature database of GLI1-altered mesenchymal tumors and identifies features that can be used for risk stratification.