Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MCmicroRNA 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.
Introduction
Embryonal tumours represent the largest category of brain cancers in children aged 0–14 years.1 Although medulloblastoma is the most common, 40% of embryonal brain tumours are rare entities primarily affecting children younger than 3–5 years and include atypical teratoid rhabdoid tumours and tumours historically categorised as supra-tentorial (sPNETs) or CNS primitive neuroectodermal brain tumours (CNS-PNETs).2, 3 Global profiling studies have shown that these rare tumours span a spectrum of molecular diseases comprising new WHO diagnostic categories.2, 4, 5, 6, 7 However, existing clinical data are difficult to evaluate as many of these entities were previously considered and treated as different diseases. Furthermore, the clinical and therapeutic spectrum of these new diseases remains poorly defined because specific molecular diagnostic assays are not routinely used. Delays in clinical recognition, diagnosis, and treatment initiation are likely to contribute substantially to the generally poor survival of children with rare brain tumours.
Research in context
Evidence before this study
We searched PubMed and Google Scholar for molecular and clinical studies of embryonal tumours with multi-layered rosettes (ETMRs) published between Nov 1, 1990, and Jan 30, 2020, using the terms “ETMR”, “ETANTR”, “ependymomblastoma” or “EP”, “medulloepithelioma” or “MEP”, “ETMR NOS”, “PNET NOS”, and the molecular annotations “C19MC”, “TTYH1”, and “LIN28A”. We reviewed clinical data for all patients with a histological diagnosis of an ETMR from studies identified by our literature search and restricted our research to English publications. ETMR is a rare, highly malignant brain tumour, previously considered as various separate histological diagnoses, and only recently designated as a distinct WHO diagnostic entity on the basis of cumulative molecular studies. Early reports described ETMRs as frequently disseminated diseases, which has led to increasing use of upfront aggressive, empirical, and experimental therapies in these patients. However, as annotated molecular and clinical data on a large patient cohort has been scarce, the full spectrum of ETMR phenotypes, clinical prognosticators, and the effect of conventional treatment modalities on patient survival has remained unclear.
Added value of this study
To our knowledge, this is the first global registry-based study of a large cohort of patients with primary ETMRs with matched annotated molecular diagnosis and detailed clinical data, providing rich phenotypic information for these patients, who exhibit a wide clinicopathological spectrum that overlaps with features of other embryonal brain tumours. Our findings highlight the importance of augmenting histological diagnosis with C19MC fluorescence in-situ hybridisation to specifically distinguish ETMRs from other infant brain tumours. We identify disease stage and location, gross total resection, and receipt of high-dose chemotherapy and radiotherapy as key prognostic factors and show that patients with ETMR with favourable clinical features treated with multi-modal therapy can have significantly improved long-term survival.
Implications of all the available evidence
Despite reports of high fatality, our study indicates that ETMRs can be curable cancers with prompt and early molecular diagnosis and intensive multi-modal therapy. In addition to informing future trial design, our study data provide a framework for clinical and diagnostic work-up, as well as therapeutic approaches to ETMRs. The data presented have immediate clinical practice implications for children diagnosed with this rare disease and should form a basis for integrative genomic studies.
A new histological category of brain tumours called embryonal tumours with abundant neuropil and true rosettes (ETANTR) were first described by Eberhart and colleagues in 2000.8 Subsequent molecular studies showed various rare histological entities diagnosed as sPNETs or CNS-PNETs, including ETANTR, medulloepithelioma, and ependymoblastoma, shared recurrent amplification or gene fusions of C19MC, a novel oncogenic microRNA locus, and primitive transcriptome enriched for LIN28A, a pluripotency factor.4, 5, 6, 9 These studies led to the designation of C19MC-altered ETMRs, and a small number of tumours without C19MC alterations (ETMR not otherwise specified), as a new WHO CNS diagnostic category.2 While fluorescence in-situ hybridisation (FISH) analyses specifically identify C19MC-altered ETMRs, ETMR not otherwise specified are more challenging to diagnose because LIN28A is expressed in other malignant paediatric brain tumours6, 10, 11 and non-CNS cancers.12, 13
ETMRs are now increasingly reported in the literature, indicating that this under-recognised entity might comprise a substantial proportion of embryonal brain tumours in infants and children younger than 3–5 years. However, due to varied prior histological labels and only recent discovery of a specific molecular diagnostic marker (C19MC), prospective treatment and outcome data for patients with ETMR are scarce. Early studies indicating that ETMRs are lethal diseases with less than 10% overall survival4, 6, 14 have led to many patients receiving empirical treatment with various aggressive conventional multi-modal and experimental therapies. The benefit of adjuvant chemotherapy and radiotherapy, reported in retrospective studies,15, 16, 17 has been difficult to assess because most studies comprise small cohorts with little treatment and survival data, and do not always have molecular diagnostic confirmation. To establish a paradigm for clinical practice and future trials, we used contemporary diagnostic methods to identify and examine the clinical, treatment, and survival characteristics of a large cohort of patients with primary ETMRs from the Rare Brain Tumor clinical registry.
Section snippets
Sample collection and analyses
The Rare Brain Tumor Consortium was established to generate a clinical registry and biorepository for rare paediatric brain tumours. From 2001 to 2019, 1904 patients aged 0–21 years with various institutional brain tumour diagnoses were enrolled by 140 participating centres with patient or parent consent, as per Research Ethics Board guidelines at the Hospital for Sick Children (Toronto, ON, Canada) and participating institutions (appendix p 5). Institutional histopathological diagnoses for
Results
Between 2001 and 2019, 1904 samples were received at the Rare Brain Tumor Consortium. 122 samples contained insufficient tissue for analysis and we reviewed histopathological diagnoses for 1782 (94%) of 1904 patients (figure 1). We identified and included only patients (n=159) with confirmed molecular diagnosis of primary ETMRs in the clinicopathological analysis. Consistent with distinct molecular identity, global methylation analyses showed ETMR (C19MC-altered and not otherwise specified)
Discussion
Although approximately 200 unique ETMR cases are recorded in systematic reviews, most reported cases have little clinical and treatment information,7, 18, 19 or do not have molecular diagnoses.17, 20 The objective of this study was to comprehensively examine clinical and therapeutic features of a large ETMR cohort with centrally confirmed molecular diagnosis, to inform clinical phenotypes, prognostic factors, and medical management of this new disease. Our data indicate ETMRs are highly
Data sharing
No individual participant data will be available. De-identified summary of basic data and dictionary are available in the appendix. Any question related to study protocol should be directed to corresponding author and can be found at the Rare Brain Tumor Consortium website.
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Only about one quarter of patients survive longer than 4–5 years (Khan et al., 2021; von Hoff et al., 2021). Inferior outcome has been shown to be related to brainstem location of the tumour and to metastatic disease at diagnosis (Friedrich et al., 2015; Horwitz et al., 2016; Juhnke et al., 2021; Khan et al., 2021; Spence et al., 2014; von Hoff et al., 2021). Metastatic spread is frequently observed during the course of disease and even extra-CNS metastases have been described (Korshunov et al., 2014; Shah et al., 2018).
The introduction of molecular methods into the diagnostics of central nervous system (CNS) tumours and the subsequent deciphering of their molecular heterogeneity has resulted in a significant impact on paediatric neurooncology. Particularly in the field of rare embryonal and sarcomatous CNS tumours, novel tumour types have been delineated and introduced in the recent 5th edition of the WHO classification of CNS tumours. The rarity and novelty of these tumour types result in diagnostic and therapeutic challenges. Apart from distinct histopathological and molecular features, these tumour types exhibit characteristic clinical properties and require different therapeutic approaches for optimal patient management. However, based on the limited availability of clinical data, current therapeutic recommendations have to be based on data from small, predominantly retrospective patient cohorts. Within this article, we provide guidance for diagnostic work-up and clinical management of rare CNS embryonal tumours (‘embryonal tumour with multi-layered rosettes’, ETMR; ‘CNS neuroblastoma, FOXR2-activated’, CNS NB-FOXR2; ‘CNS tumour with BCOR-ITD, CNS BCOR-ITD) and rare CNS sarcomatous tumours (‘primary intracranial sarcoma, DICER1-mutant’, CNS DICER1; ‘CIC-rearranged sarcoma’, CNS CIC). By emphasizing the significant consequences on patient management in paediatric CNS tumours, we want to encourage wide implementation of comprehensive molecular diagnostics and stress the importance for joint international efforts to further collect and study these rare tumour types.
