Background

Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease.

Methods

Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors.

Findings

159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p<0·0001) on multivariable analysis. 2-year event-free and overall survival was 0% at 2 years in patients treated with conventional chemotherapy without radiotherapy (regardless of surgery extent), and 21% (95% CI 1–41) and 30% (6–54), respectively, in patients treated with high-dose chemotherapy, and gross total resection without radiotherapy. 2-year event-free survival in patients treated with high-dose chemotherapy and radiotherapy was 66% (95% CI 39–93) for patients with gross total resection and 44% (7–81) for patients with sub-total resection. 2–5-year overall survival was 66% (95% CI 33–99, p=0·038) for patients with gross total resection and 67% (36–98, p=0·0020) for patients with sub-total resection.

Interpretation

Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival.

Funding

Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

中文翻译：

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具有多层玫瑰花结的胚胎性肿瘤的临床表型和预后特征：一项罕见的脑肿瘤登记研究

背景

具有多层玫瑰花结 (ETMR) 的胚胎性肿瘤是一种新发现的罕见儿科脑肿瘤，其C19MC microRNA 基因座发生了改变。由于不同的诊断实践和稀缺的临床数据，这些肿瘤的疾病特征和结果的决定因素不明确。我们对原发性 ETMR 进行了综合临床病理学和分子分析，以确定临床表型，并确定这种孤儿疾病的生存预后因素和关键治疗方式。

方法

具有可用于分析的原发性 ETMR 和组织的儿科患者是从罕见的脑肿瘤联盟全球登记处确定的。根据当前的 WHO CNS 肿瘤指南，使用组织病理学和分子检测对机构组织病理学诊断进行了集中重新审查。只有在 2019 年 11 月 30 日具有完整临床、治疗和生存数据的患者才被纳入临床病理分析。在接受主要多模式治疗方案的患者中，使用 Cox 比例风险和对数秩分析确定无事件生存期和总生存期。使用单变量和多变量 Cox 比例风险回归来估计临床、分子或治疗相关预后因素的 95% CI 的风险比 (HR)。

发现

159 名患者确诊为原发性 ETMR（诊断时的中位年龄 26 个月，IQR 18-36），并被纳入我们的临床病理分析。ETMR 主要是非转移性的（128 名患者中的 94 名 [73%]），来自多个部位；154 例中有 84 例（55%）是脑肿瘤，154 例中有 70 例（45%）出现在其他脑肿瘤的特征部位。霍尔马克C19MC159 名患者中有 144 名 (91%) 出现改变；15 (9%) 是未另外指定的 ETMR。在接受治愈性治疗的患者中，6 个月时的无事件生存率为 57%（95% CI 47-68），2 年时为 31%（21-42）；2 年总生存率为 29% (20-38)，4 年总生存率为 27% (18-37)。总生存期与非转移性疾病（HR 0·48，95% CI 0·28-0·80；p=0·0057）和非脑干位置（0·42 [0·22-0·81]）相关; p=0·013) 单变量分析，以及总切除术 (0·30, 0·16–0·58; p=0·0014), 高剂量化疗 (0·35, 0·19 –0·67；p=0·0020）和放疗（0·21，0·10–0·41；p<0·0001）在多变量分析中。接受常规化疗但不接受放疗的患者（无论手术程度如何），2 年无事件和 2 年总生存率为 0%，在接受高剂量化疗和未接受放疗的大体全切除治疗的患者中，分别为 21% (95% CI 1-41) 和 30% (6-54)。在接受大剂量化疗和放疗的患者中，大剂量全切除患者的 2 年无事件生存率为 66% (95% CI 39-93)，次全切除患者为 44% (7-81)。大体全切除患者的 2-5 年总生存率为 66%（95% CI 33-99，p=0·038），次全切除患者为 67%（36-98，p=0·0020）切除。

解释

及时的分子诊断和术后治疗以及针对患者特定风险特征的强化多模式治疗可以提高 ETMR 生存率。

资金

加拿大健康研究所、加拿大研究主席奖、澳大利亚狮子会儿童癌症研究基金会、西班牙儿科学会、安达卢西亚军政府协会、Miracle Marnie、Phoebe Rose Rocks、Tali's Funds、Garron Cancer Centre、Grace's Walk 、Meagan's Hug、Brainchild、Nelina's Hope 和 Jean Martel 基金会。