Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric Brain Tumour Consortium experience

doi:10.1016/j.ejca.2011.09.005

European Journal of Cancer

Volume 48, Issue 3, February 2012, Pages 353-359

https://doi.org/10.1016/j.ejca.2011.09.005 Get rights and content

Abstract

Background

Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1–4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors.

Patients and methods

A national retrospective study of children ⩽18 years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review.

Results

There were 50 patients (31 males; median age at diagnosis of 16.7 months). Twelve patients were >36 months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation.

Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5 months (0–32). The median survival time of the entire cohort was 13.5 months (1–117.5 months).

Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2 years overall survival (OS): 60% ± 12.6 versus 21.7% ± 8.5, p = 0.03). HDC conferred better outcome (2 years OS 47.9% ± 12.1 versus 27.3% ± 9.5, p = 0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation.

Conclusion

The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.

Introduction

Since their first description in the mid 1980s, atypical teratoid rhabdoid tumours (ATRT) of the central nervous system (CNS) are increasingly recognised and are now routinely diagnosed despite their rarity.5, 6, 7 These brain tumours that mostly affect infants and young children have historically been characterised by an aggressive behaviour and a grim prognosis with a median survival ranging from 6 to 11 months.3, 8, 9 Given the rarity of the disease, our current knowledge is mostly based on small series with a limited number of patients. No definitive guidelines have been established that reflect optimal treatment. Most recent treatment strategies recommend maximal surgical resection followed by intensive chemotherapy with or without intrathecal chemotherapy and focal or craniospinal radiation. Although early results of pilot studies have shown encouraging results, the respective contribution of each modality in improved outcome is unclear. In the past 5 years treatment approaches in Canada have been relatively homogeneous and based on the use of high dose chemotherapy. The use of adjuvant radiation from centre with an even distribution of children subjected or not to radiation. With this large centrally reviewed national cohort, our aim was to provide population-based data on this entity to better define prognostic factors and highlight new trend in outcome.

Section snippets

Patients

This retrospective study was conducted through the Canadian Paediatric Brain Tumour Consortium (CPBTC), a network of 17 Canadian Paediatric centres collaborating in paediatric neuro-oncology research. After approval from their respective institutional review board, each participating centre was asked to provide anonymised clinical data and pathology tumour slides on patients, aged between 0 and 18 years, and locally diagnosed with CNS ATRT between 1995 and 2007. Data collection forms inquired

Results

Among the 17 institutions of the CPBTC, 6 had no patients eligible for the study. Data were obtained from 10 out 11 remaining centres.

Discussion

This national registry represents one of the largest population-based series of CNS ATRT reported to date. The central pathology review ensured the homogeneity of this retrospective series. Although we collected cases from 1995 onwards, a period during which this entity was better recognised, it is likely that our survey underestimated the total number of Canadian CNS ATRT, since the central pathology review did not include all embryonal tumours diagnosed during the study.2, 10

Unlike voluntary

Conclusion

Despite the well recognised dismal prognosis associated with CNS ATRT, a trend to improved outcome is emerging with the use of multimodalities strategies and the data from our national cohort to support that trend. Furthermore our series highlights the encouraging results associated with the use of high dose chemotherapy and describe a proportion of long term survivors (50%) who did not receive radiation.

Conflict of interest statement

None declared.

Acknowledgements

This work has been supported by a research grant from B.R.A.I.N. Child (Brain Tumor Research Assistance and information Network).

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Radiation Therapy Plays an Important Role in the Treatment of Atypical Teratoid/Rhabdoid Tumors: Analysis of the EU-RHAB Cohorts and Their Precursors
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Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignancy of the central nervous system in young children with a dismal prognosis. Prognostic markers have been extensively investigated but have not been validated. The role of radiation therapy (RT) remains controversial. We evaluated the impact of RT as part of multimodality treatment by analyzing data of a European AT/RT cohort.
We retrospectively analyzed data of the European Registry for Rhabdoid Tumors and its precursors. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Potential impact of prognostic factors was analyzed using univariable and multivariable Cox regression analyses with RT as a time-dependent factor.
Data of 186 children (118 male, 68 female) treated from 1990 to 2016 were evaluable. The median age at diagnosis was 1.57 years (range, 0.01-26.70 years); 47% (87/186) of the patients were under the age of 18 months. Sixty-nine percent (128/186) received RT (focal RT, n = 93; craniospinal treatment with local boost, n = 34; spinal irradiation, n = 1). The median follow-up duration of the entire cohort was 1.73 years (range, 0.06-20.11 years). The estimated PFS and OS rates were 48% (95% CI, 41%-55%) and 72% (95% CI, 65%-78%) at 1 year and 33% (95% CI, 26%-40%) and 49% (95% CI, 41%-56%) at 2 years, respectively. On multivariable analysis, RT was an independent significant prognostic factor for PFS (hazard ratio, 0.45; 95% CI, 0.27-0.75; P = .002) and OS (hazard ratio, 0.54; 95% CI, 0.32-0.93; P = .025).
This analysis confirms the relevance of local therapies. RT was an independent prognostic factor for outcomes in children experiencing AT/RT. However, long-term sequelae have to be carefully evaluated and considered given the young age at time of RT.
Management of Atypical Teratoid/Rhabdoid Tumors in the Pediatric Population: A Systematic Review and Meta-Analysis
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Atypical teratoid/rhabdoid tumors are rare and aggressive tumors that mainly affect children <3 years of age. Despite aggressive treatment, the overall survival rate for pediatric atypical teratoid/rhabdoid tumors remains poor. Due to their rarity, little is known regarding prognostic factors, and there is no official standard of treatment.
A comprehensive database search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Search terms included “atypical teratoid rhabdoid tumor” and “atypical (teratoid OR rhabdoid) tumor.” Variables of interest included, but were not limited to, age, sex, tumor location, treatment modality, extent of resection, and overall survival.
The study included 294 articles and 936 patients. The median age of patients was 22 months. There was a significant difference in survival among patients receiving surgery compared with patients receiving nonoperative treatment (50.3 months vs. 28 months; P < 0.005). Extent of resection did not significantly improve survival (P = 0.832 for gross total resection, P = 0.650 for partial resection). Combination therapy with surgical resection, radiotherapy, and chemotherapy demonstrated the largest median overall survival (54.9 months) and significantly improved survival on multivariate analysis (hazard ratio, 0.48; 95% confidence interval, 0.23–0.97; P = 0.042).
The results of this study indicate that while surgery is a crucial treatment modality for pediatric atypical teratoid/rhabdoid tumors, the effect of extent of resection is unclear. Multimodal therapy including surgery, radiotherapy, and chemotherapy is effective in improving overall survival. Future studies should focus on using larger datasets to efficiently account for confounding factors and biases.
Rare pediatric brain tumors
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There are a large variety of rare pediatric brain tumors, but we limit ourselves to three which pediatric oncologists are likely to encounter at some point in their career. CNS rhabdoid and choroid plexus tumors are aggressive with generally poor survival, and their management is discussed, along with advances in the field of molecular pathology, and multi-institutional trials which have allowed some improvement in outcome. Craniopharyngioma is a more indolent tumor, and the diagnosis and management is discussed along with the impact that imaging and neurosurgical technique is having on improving outcomes. Late-effects remain troublesome in patients with any of the three diagnoses.
The Impact of Surgical Resection and Adjuvant Therapy on Survival in Pediatric Patients with Atypical Teratoid/Rhabdoid Tumor: Systematic Review and Pooled Survival Analysis
2022, World Neurosurgery
Citation Excerpt :
Most published data on outcomes of patients with ATRT are from small series and are retrospective. Initial retrospective studies reported an average survival from diagnosis of only about 12 months.12-16 In a retrospective report, 2-year overall survival (OS) was better for patients who underwent a gross total resection (GTR) than for those who had a subtotal resection (STR).
Atypical teratoid/rhabdoid tumor (ATRT) is a rare malignant neoplasm in the pediatric population. ATRT is characterized by rhabdoid cells combined with the loss of either the INI1 (integrase interactor 1) or BRG1 (Brahma-related gene-1) protein.
To systematically review and analyze patient and tumor characteristics, prognosis, and impact of treatment on survival in pediatric patients with ATRT confirmed by alterations in INI1 or BRG1. This systematic review is the first to include only pediatric cases of ATRT confirmed with either INI1 or BRG1 alterations.
MEDLINE was searched using the terms "atypical teratoid/rhabdoid tumor" AND "paediatric/pediatric." Cases were included if confirmed by loss of INI1 or BRG1. The extracted dataset was analyzed using descriptive statistics, log-rank test, and Kaplan-Meier survival analysis via SPSS.
A total of 38 articles were included in this study. The average age at diagnosis was 3 years. The most common locations reported are the supratentorial region and cerebral hemispheres. Ninety-three patients were reported to show evidence of dissemination. The average overall survival was 29 months. A significant difference in survival was noted between the tumor location groups, particularly worse outcomes for patients with spinal ATRT (P < 0.001). Extent of resection and adjuvant therapy were significant for survival (χ² = 10.107, P = 0.018 and χ² = 20.38, P < 0.0001, respectively).
ATRT of the central nervous system in pediatric populations is a rare neoplasm associated with a poor prognosis in most patients. Future studies should be directed to find a standardized treatment protocol.
Evaluation of targeting autophagy for the treatment of malignant rhabdoid tumours
2022, Cancer Treatment and Research Communications
Citation Excerpt :
The patients’ age poses significant restrictions when planning intensive therapy due to their low tolerance to radiotherapy and chemotherapy. This, combined with the higher stage at presentation means that the prognosis for MRT is very poor with an estimated 2-year survival rate of 30% [7–9]. Collectively, this indicates that there is an urgent need to better understand the molecular mechanisms underlying chemoresistance in rhabdoid tumours to reduce the toxicities associated with aggressive chemotherapeutic regimens in young children.
Malignant rhabdoid tumour (MRT) is a rare and aggressive paediatric tumour that typically arises in the kidneys or central nervous system (CNS). The malignancy often affects patients under the age of three and is associated with an extremely poor survival rate, with most deaths occurring within the first year of presentation. Thus, there is an unmet and urgent medical need for novel therapeutic strategies for this malignancy. One of the major issues when treating MRT patients is the emergence of chemoresistance. Autophagy has become an area of focus in the study of chemoresistance due to its reported dual role as both a pro-survival and pro-death mechanism. The role of autophagy in the chemotherapeutic response of MRT remains largely unknown. A greater understanding of the role of autophagy may lead to the development of therapeutic strategies to enhance chemotherapeutic effect and improve the clinical outcome of MRT patients. This study evaluated the cellular response to cisplatin, a representative chemotherapeutic agent used in the treatment of MRT, and the role of autophagy in mediating cisplatin resistance. Our results demonstrated that cisplatin induced apoptosis and autophagy concomitantly in a panel of MRT cell lines. Furthermore, inhibition of caspase-induced apoptosis with Z-VAD-FMK also inhibited autophagy levels demonstrating a complex interplay between these two pathways. In addition, blocking autophagy at the early stages of the autophagic process using the pharmacological inhibitor SAR405 or through the genetic knockdown of critical autophagic protein ATG5 by siRNA did not sensitise cells to cisplatin-induced apoptosis. Collectively, these results suggest that induction of autophagy does not appear to elicit a pro-survival effect in the chemotherapeutic response of MRT cells.
Targeting inhibitor of apoptosis proteins (IAPs) with IAP inhibitors sensitises malignant rhabdoid tumour cells to cisplatin
2022, Cancer Treatment and Research Communications
Malignant rhabdoid tumour (MRT) is a rare, aggressive paediatric malignancy most commonly diagnosed in those below the age of three. MRTs can arise in soft tissue but are more often associated with the central nervous system or kidney. Unfortunately, the prognosis upon diagnosis with MRT is poor. Given the resistance of MRT to current treatment protocols including cisplatin, and the vulnerability of this young patient population to aggressive therapies, there is a need for novel treatment options. Several members of the inhibitor of apoptosis protein (IAP) family including X‑linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/cIAP2), livin and survivin have been implicated in chemotherapy resistance in various malignancies. We have previously demonstrated expression of these IAP family members in a panel of MRT cell lines. In the present study, sensitivity of this same panel of MRT cell lines to small-molecule mediated inhibition of the IAPs via the survivin inhibitor YM155 and the XIAP/cIAP1/cIAP2 inhibitor BV6 was demonstrated. Additionally, both BV6 and the XIAP inhibitor embelin synergistically enhanced cisplatin mediated apoptotic cell death in MRT cell lines, with enhanced caspase-3 cleavage. Importantly, we have demonstrated, for the first time, expression of XIAP, its target caspase-3 and its endogenous inhibitor SMAC in rhabdoid tumour patient tissue. In conclusion, this study provides pre-clinical evidence that IAP inhibition may be a new therapeutic option in MRT.

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Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric Brain Tumour Consortium experience

Abstract

Background

Patients and methods

Results

Conclusion

Introduction

Section snippets

Patients

Results

Discussion

Conclusion

Conflict of interest statement

Acknowledgements

Hum Pathol.

Int J Radiat Oncol Biol Phys

Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry

J Clin Oncol

Incidence of atypical teratoid/rhabdoid tumors in children: a population-based study by the Austrian Brain Tumor Registry, 1996–2006

Cancer

Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor

J Clin Oncol

Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy

J Clin Oncol

Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood

J Neurooncol

Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study

Am J Surg Pathol

Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop

J Pediatr Hematol Oncol

Atypical teratoid rhabdoid tumors of childhood: diagnosis, treatment and challenges

Expert Rev Anticancer Ther

Redefining inidence, outcome and prognostic factors in CNS atypical teratoid rhabdoid tumors at BC children’s hospital

Neuro Oncol

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group

J Clin Oncol