Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by extensive brain invasion and rarely, systemic metastases. The pathogenesis of metastatic glioblastoma is largely unknown. We present the first integrated clinical/histologic/genetic analysis of 5 distinct brain and lung foci from a unique case of recurrent, multifocal, multicentric and metastatic glioblastoma. The initial right frontotemporal gliosarcoma received standard surgical/chemoradiation therapy and recurred 1.5 years later, co-occurring with three additional masses localized to the ipsilateral temporal lobe, cerebellum and lung. Synchronous metastatic lung carcinoma was suspected in this long-term smoker patient with family history of cancer. However, glioblastoma was confirmed in all tumors, although with different morphologic patterns, including ependymomatous and epithelioid. Genomic profiling revealed a germline FANCD2 variant of unknown significance, and a 4-gene somatic mutation signature shared by all tumors, consisting of TERT promoter and PTEN, RB1 and TP53 tumor suppressor mutations. Additional GRIN2A and ATM heterozygous mutations were selected in the cerebellar and lung foci, but were variably present in the supratentorial foci, indicating reduced post-therapeutic genetic evolution in brain foci despite morphologic variability. Significant genetic drift characterized the lung metastasis, likely explaining the known resistance of circulating glioblastoma cells to systemic seeding. MET overexpression was detected in the initial gliosarcoma and lung metastasis, possibly contributing to invasiveness. This comprehensive analysis sheds light on the temporospatial evolution of glioblastoma and underscores the importance of genetic testing for diagnosis and personalized therapy.

中文翻译：

---

复发性，多灶性，多中心性和转移性胶质母细胞瘤的遗传和组织学时空演变。

胶质母细胞瘤是最常见和侵略性的原发性脑肿瘤，其特征是广泛的脑部浸润，很少发生全身转移。转移性胶质母细胞瘤的发病机理很大程度上未知。我们从复发性，多灶性，多中心性和转移性胶质母细胞瘤的独特病例中，对5个不同的脑和肺灶进行了首次综合临床/组织学/遗传学分析。最初的右额颞部神经胶质肉瘤接受了标准的外科手术/化学放射治疗，并于1.5年后复发​​，并伴有位于同侧颞叶，小脑和肺部的三个附加肿块。在这名有家族癌症史的长期吸烟患者中，怀疑是同步转移性肺癌。但是，尽管形态不同，但在所有肿瘤中都证实了胶质母细胞瘤，包括室上皮和上皮样。基因组分析显示出未知的种系FANCD2变体，以及所有肿瘤共有的4基因体细胞突变特征，包括TERT启动子和PTEN，RB1和TP53抑癌突变。在小脑和肺病灶中选择了其他GRIN2A和ATM杂合突变，但在幕上病灶中存在差异，表明尽管形态上存在变异，但脑病灶中治疗后遗传进化的减少。明显的遗传漂移是肺转移的特征，可能解释了循环胶质母细胞瘤细胞对全身接种的已知抗性。在最初的胶质肉瘤和肺转移中检测到MET过表达，这可能有助于浸润。