Swabian Children's Cancer Center, University Hospital Augsburg, Augsburg, Germany.
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, Bonn, Germany.
Int J Cancer. 2020 Oct 15;147(8):2159-2175. doi: 10.1002/ijc.32995. Epub 2020 May 1.
Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.
报告显示，儿童低级别弥漫性神经胶质瘤（WHO 分级 II 级，简称 DG2）患者的生存率较低，但对于遗传定义的 DG2 实体，其结果尚无定论。我们分析了 DG2 的自然病史、治疗方法和预后，并研究了哪些遗传定义的亚实体对生存不利。在前瞻性注册的、基于人群的德国/瑞士 SIOP-LGG 2004 队列中，有 100 名患者（年龄 0.8-17.8 岁，4%患有神经纤维瘤病 [NF1]）被诊断为 DG2。在活检（41%）或不同程度的切除（59%）后，65 名患者未接受辅助治疗。放射学进展或严重神经症状促使 18 名患者接受化疗，17 名患者接受放疗。35 名患者中有 19 名需要进行多次挽救性治疗。5 年无事件生存率降至 0.44，5 年总生存率为 0.90（中位观察时间为 8.3 年）。对 65/100 名 DG2 患者进行广泛的遗传分析，发现 4 名患者存在组蛋白 3-K27M 突变，11 名患者存在 IDH1 突变，12 名患者存在 BRAF-V600 突变，6 名患者存在 KIAA1549-BRAF 融合，而其余 32 名肿瘤组织未显示这些基因的改变。除携带 KIAA1549-BRAF 融合的肿瘤外，所有遗传定义亚组的肿瘤在 0.5 至 10.8 年内均进展为恶性胶质瘤，其中包括 12 例。组蛋白 3-K27M 突变肿瘤在 0.6 至 2.4 年内均为致命性的。目前的 LGG 治疗策略似乎适用于所有 DG2 实体，除了需要 HGG 相关治疗策略的组蛋白 3-K27M 突变肿瘤外。我们的数据证实了对儿童低级别弥漫性神经胶质瘤进行遗传定义的重要性，以便做出适当的治疗决策和风险评估。
