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Abstract：
The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2-3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10-). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10-, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.
摘要：
世界卫生组织中枢神经系统肿瘤分类最近纳入了组织学特征，免疫表型,和分子特征来提高胶质母细胞瘤(GBM)诊断的准确性。FGFR3::TACC3(F3T3)融合已被鉴定为IDH-野生型GBM中的致癌驱动因子。最近的研究已经证明了在临床试验中使用FGFR抑制剂和在GBM治疗的临床前模型中使用TACC3靶向剂的潜力。然而,关于具有F3T3融合的IDH-野生型GBM的临床病理和遗传特征的信息有限。这项研究的目的是全面调查临床表现，组织学特征，和F3T3阳性GBM的突变谱。在2017年9月至2023年2月之间，从504例IDH野生型GBM中连续提取了25例（5.0％）F3T3阳性GBM。对25例原发性F3T3阳性GBMs和4例复发性F3T3阳性GBMs的临床病理信息和靶向测序结果进行了评估，并与F3T3阴性GBMs的比较。仅通过组织学确定的临时等级分布如下：4（26/29；89.7％），3（2/29；6.9%），和2（1/29；3.4％）。基于TERT启动子突变的鉴定以及7号染色体的合并获得和10号染色体的丢失(7+/10-),2-3级肿瘤最终被诊断为4级GBM。F3T3阳性GBM主要影响女性（每个男性2.6女性）。初始诊断时F3T3阳性GBM患者的平均年龄为62岁。与F3T3阴性GBM相比，F3T3阳性GBM在皮质部位的发生率更高。影像学研究显示，超过三分之一（12/29；41.4%）的F3T3阳性GBM显示出肿瘤边界。随访时间超过20个月的17名患者中有7名（41.2％）死于该疾病。组织学上,F3T3阳性GBM更频繁地显示曲线毛细血管增殖，栅栏核，和钙化与F3T3阴性GBM相比。分子，在F3T3阳性GBM中观察到的最常见的改变是TERT启动子突变和7+/10-，而EGFR的扩增，PDGFRA,根本没有检测到KIT。其他遗传改变包括CDKN2A/B缺失，PTEN突变,TP53突变,CDK4扩增,和MDM2扩增。我们的观察表明F3T3阳性GBM是IDH野生型GBM的独特分子亚组。临床医生和病理学家都应在弥漫性星形胶质细胞瘤的鉴别诊断中考虑这种罕见的实体，以做出准确的诊断并确保适当的治疗管理。
