GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.

中文翻译：

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对 GLI1 改变的间质肿瘤进行全面的临床病理学和分子重新评估，汇总结果分析显示 GLI1 扩增肿瘤与 GLI1 重排肿瘤的生存率较差。


GLI1 改变的间质肿瘤是最近描述的一种独特的病理实体，具有确定的恶性肿瘤风险，通过 GLI1 基因融合或扩增进行分子定义。由两种看似不同的 GLI1 激活机制驱动的肿瘤临床病理学重叠仍在不断出现。在此，我们报告了迄今为止最大的一系列分子证实的 GLI1 改变的间质肿瘤，包括 23 个 GLI1 扩增和 15 个 GLI1 重排的新病例，并进行了比较临床病理学、基因组和生存研究。 GLI1 重排的肿瘤发生在年轻患者中（42 岁与 52 岁），并且与 GLI1 扩增的肿瘤相比更大（分别为 5.6 厘米与 1.5 厘米）。两组之间的组织学特征总体相似，显示出多结节模式和上皮样巢状结构，以及较少见的梭形细胞，周围有丰富的毛细血管网络。在 3 个 GLI1 扩增的肿瘤中发现了明显的旋转模式。两组均很少见到分散的多形性巨细胞。免疫图谱显示 CD56 的表达一致，而 S100、CD10 和 SMA 的表达存在差异。从基因组角度来看，两组的突变负担总体较低，罕见的 TP53 突变仅在 GLI1 扩增的肿瘤中可见。与去分化脂肪肉瘤相比，GLI1 扩增的间充质肿瘤在 12q13-15 位点大多表现出单个扩增子，去分化脂肪肉瘤表现出以 CDK4 (12q14.1) 和 MDM2 (12q15) 为中心的 2 峰扩增。与 GLI1 重排的肿瘤相比，GLI1 扩增的肿瘤具有显着更高的 GLI1 mRNA 表达。对当前和已发表病例 (n=83) 的生存汇总分析显示，GLI1 扩增患者的总生存率较差，16% 的患者死于疾病，而 1% 的患者死于疾病。GLI1 重排组中有 7%。尽管进展率相当，但与 GLI1 重排肿瘤相比，GLI1 扩增肿瘤的中位无进展生存期较短（25 个月 vs. 77 个月）。单变量分析显示，传统的恶性肿瘤组织学预测因子（有丝分裂计数≥4/10高倍视野、坏死的存在和肿瘤大小≥5cm）与GLI1改变的间叶性肿瘤的预后较差相关。