A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1 -altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1 - amplified Versus GLI1- rearranged Tumors.

IF 4.5 1区 医学 Q1 PATHOLOGY American Journal of Surgical Pathology Pub Date : 2024-10-01 Epub Date: 2024-06-27 DOI:10.1097/PAS.0000000000002272
Carla Saoud, Abbas Agaimy, Josephine K Dermawan, Jie-Fu Chen, Marc K Rosenblum, Brendan C Dickson, Nooshin Dashti, Michael Michal, Kemal Kosemehmetoglu, Nasir Ud Din, Karen Albritton, Narasimhan P Agaram, Cristina R Antonescu
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Abstract

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.

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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再评估,结果显示GLI1扩增肿瘤的生存率低于GLI1重组肿瘤。
GLI1改变的间质瘤是最近描述的一种独特病理实体,具有既定的恶性风险,其分子定义为GLI1基因融合或扩增。这两种看似不同的 GLI1 激活机制导致的肿瘤的临床病理重叠仍在不断出现。在此,我们报告了迄今为止经分子证实的最大规模的GLI1改变间叶肿瘤系列,包括23例GLI1扩增和15例GLI1重排新病例,并进行了临床病理学、基因组学和生存率的比较研究。GLI1重组肿瘤发生在较年轻的患者中(42岁对52岁),与GLI1扩增肿瘤相比体积更大(分别为5.6厘米对1.5厘米)。两组患者的组织学特征总体相似,均表现为多结节型和上皮样细胞(较少见的是纺锤形细胞)巢状结构,周围有丰富的毛细血管网。在 3 个 GLI1 扩增的肿瘤中发现了明显的轮状模式。两组肿瘤中都很少见到散在的多形性巨细胞。免疫图谱显示 CD56 表达一致,S100、CD10 和 SMA 表达不一。从基因组学来看,两组肿瘤的基因突变负担总体较低,只有在GLI1扩增的肿瘤中出现罕见的TP53突变。GLI1扩增的间质瘤大多在12q13-15位点表现出单个扩增子,相比之下,去分化脂肪肉瘤则表现出以CDK4(12q14.1)和MDM2(12q15)为中心的双峰扩增。与GLI1重组肿瘤相比,GLI1扩增肿瘤的GLI1 mRNA表达量明显更高。对现有病例和已发表病例(n=83)进行的生存期汇总分析表明,GLI1扩增患者的总生存期较差,16%的患者死于疾病,而GLI1重组组仅为1.7%。尽管进展率相当,但与GLI1重组肿瘤相比,GLI1扩增肿瘤的中位无进展生存期更短(25个月对77个月)。单变量分析表明,传统的恶性肿瘤组织学预测指标(有丝分裂计数≥4/10个高倍视野、出现坏死、肿瘤大小≥5厘米)与GLI1改变间质肿瘤的较差预后有关。
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来源期刊
CiteScore
10.30
自引率
5.40%
发文量
295
审稿时长
1 months
期刊介绍: The American Journal of Surgical Pathology has achieved worldwide recognition for its outstanding coverage of the state of the art in human surgical pathology. In each monthly issue, experts present original articles, review articles, detailed case reports, and special features, enhanced by superb illustrations. Coverage encompasses technical methods, diagnostic aids, and frozen-section diagnosis, in addition to detailed pathologic studies of a wide range of disease entities. Official Journal of The Arthur Purdy Stout Society of Surgical Pathologists and The Gastrointestinal Pathology Society.
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