Primary brain tumors, including atypical teratoid/rhabdoid tumors, are a diverse group of diseases that together constitute the most common solid tumor of childhood. The PDQ childhood brain tumor treatment summaries are primarily organized according to the World Health Organization classification of nervous system tumors.[1,2] Brain tumors are classified according to histology, but immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Tumor location and extent of spread are important factors that affect treatment and prognosis. For a description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
CNS atypical teratoid/rhabdoid tumor (AT/RT) is a rare, clinically aggressive tumor that most often affects children aged 3 years and younger but can occur in older children and adults. Approximately one-half of AT/RTs arise in the posterior fossa. The diagnostic evaluation includes magnetic resonance imaging (MRI) of the neuraxis and lumbar cerebrospinal fluid examination. AT/RT has been linked to somatic and germline mutations of SMARCB1 and, less commonly, SMARCA4, both of which are tumor suppressor genes. There is no current standard treatment for children with AT/RT. Multimodality treatment consisting of surgery, chemotherapy, and radiation therapy is under evaluation.
Based on present biological understanding, AT/RT is part of a larger family of rhabdoid tumors. In this summary, the term AT/RT refers to CNS tumors only and the term rhabdoid tumor reflects the possibility of both CNS and non-CNS tumors. Unless specifically noted in the text, this summary is referring to CNS AT/RT.
Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
The exact incidence of childhood CNS AT/RT is difficult to determine because the tumor is rare and has only been recognized since 1996.
The incidence in older patients is unknown. However, in the Central Nervous System Atypical Teratoid/Rhabdoid Tumor Registry (AT/RT Registry), 12 of the 42 patients (29%) were older than 36 months at the time of diagnosis.
Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.
Approximately one-half of all AT/RTs arise in the posterior fossa, although it can occur anywhere in the CNS.[3,6] Tumors of the posterior fossa may occur in the cerebellopontine angle or more midline. Involvement of individual cranial nerves has been noted.
Because AT/RT grows rapidly, patients typically have a fairly short history of progressive symptoms, measured in days to weeks. Signs and symptoms depend on tumor location. Young patients with posterior fossa tumors usually present with symptoms related to hydrocephalus, which include the following:
They may also develop ataxia or regression of motor skills.
Registry data suggest that up to 30% of patients present with disseminated disease.[9,12,13] Dissemination is typically through leptomeningeal pathways seeding the spine and other areas of the brain. Up to 35% of patients present with germline mutations and may be prone to synchronous, multifocal tumors. There are also rare reports of patients with synchronous renal rhabdoid tumors and CNS AT/RTs.[14,15,16,17]
All patients with suspected childhood AT/RT should undergo MRI of the brain and spine. Unless medically contraindicated, the lumbar cerebrospinal fluid should be inspected for evidence of tumor. Patients may also undergo renal ultrasonography to detect synchronous tumors.
AT/RTs cannot be reliably distinguished from other malignant brain tumors on the basis of clinical history or radiographic evaluation alone. Surgery is necessary to obtain tissue and confirm the diagnosis. Immunohistochemical staining for loss of SMARCB1 protein expression is also used to confirm the diagnosis.[18,19]
Prognostic factors that affect survival for patients with AT/RTs are not fully delineated.
Known factors associated with a poor outcome include the following:
Most published data on outcomes of patients with AT/RT are from small series and are retrospective in nature. Initial retrospective studies reported an average survival from diagnosis of only about 12 months.[5,6,10,22,23] In a retrospective report, 2-year overall survival (OS) was better for patients who underwent a gross-total resection than for those who had a subtotal resection. However, in this study, the effect of radiation therapy on survival was less clear.
Childhood central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) was first described as a discrete clinical entity in 1987  on the basis of its distinctive pathological and genetic characteristics. Before then, it was most often classified as a medulloblastoma, CNS primitive neuroectodermal tumor (CNS PNET), or choroid plexus carcinoma. The World Health Organization (WHO) classifies AT/RT as an embryonal grade IV neoplasm.
Histologically, AT/RT is morphologically heterogeneous, typically containing sheets of large epithelioid cells with abundant eosinophilic cytoplasm and scattered rhabdoid cells, most often with accompanying components of primitive neuroectodermal cells (small round blue cells), mesenchymal cells, and/or glial cells.
Immunohistochemical staining for epithelial markers (cytokeratin or epithelial membrane antigen), glial fibrillary acidic protein, synaptophysin (or neurofilament), and smooth muscle (desmin) may help to identify the heterogeneity of differentiation, but will vary depending on the cellular composition. Rhabdoid cells, while not present in all AT/RTs, will express vimentin, epithelial membrane antigen, and smooth muscle actin.
Immunohistochemical staining for the SMARCB1 protein is useful in establishing the diagnosis of AT/RT. A loss of SMARCB1 staining is noted in neoplastic cells, but staining is retained in non-neoplastic cells (e.g., vascular endothelial cells).[5,6,7]
AT/RT is a rapidly growing tumor that can have an MIB-1 labeling index of 50% to 100%.
Genomics of CNS Atypical Teratoid/Rhabdoid Tumor (AT/RT)
AT/RT was the first primary pediatric brain tumor in which a candidate tumor suppressor gene, SMARCB1 (previously known as INI1 and hSNF5), was identified.SMARCB1 is genomically altered in most rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.SMARCB1 is a component of a SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex.
Rare cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 mutations have also been associated with somatic or germline mutations of SMARCA4/BRG1, another member of the SWI/SNF chromatin-remodeling complex.[7,11,12]
The 2016 WHO classification defines AT/RT by the presence of either SMARCB1 or SMARCA4 alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed CNS embryonal tumor with rhabdoid features.
Despite the absence of recurring genomic alterations beyond SMARCB1 and SMARCA4,[13,14,15] biologically distinctive subsets of AT/RT have been identified.[16,17] The following three distinctive subsets of AT/RT were identified through the use of DNA methylation arrays for 150 AT/RT tumors and gene expression arrays for 67 AT/RT tumors:
Cribriform neuroepithelial tumor is a brain cancer that also presents in young children and has genomic and epigenomic characteristics that are very similar to AT/RT TYR. (Refer to the Cribriform Neuroepithelial Tumor section of the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information.)
In addition to somatic mutations, germline mutations in SMARCB1 have been reported in a substantial subset of patients with AT/RT.[9,20] A study of 65 children with rhabdoid tumors found that 23 (35%) had germline mutations and/or deletions of SMARCB1. Children with germline alterations in SMARCB1 presented at an earlier age than did sporadic cases (median age, approximately 5 months vs. 18 months) and were more likely to present with synchronous, multifocal tumors. One parent was found to be a carrier of the SMARCB1 germline abnormality in 7 of 22 evaluated cases showing germline alterations, with four of the carrier parents being unaffected by SMARCB1-associated cancers. This indicates that AT/RT shows an autosomal dominant inheritance pattern with incomplete penetrance.
Gonadal mosaicism has also been observed, as evidenced by families in which multiple siblings are affected by AT/RT and have identical SMARCB1 alterations, but both parents lack a SMARCB1 mutation/deletion.[5,6] Screening for germline SMARCB1 mutations in children diagnosed with AT/RT is suggested for counseling families on the genetic implications of their child's AT/RT diagnosis. Preliminary recommendations for the genetic evaluation and subsequent presymptomatic screening of nonaffected mutation carriers (including parents and siblings of affected patients) have been reported and are likely to evolve as the understanding of rhabdoid tumor predisposition improves. In patients with a predisposition to AT/RT, whole-body MRI may help to identify synchronous rhabdoid tumors outside of the CNS.
Loss of SMARCB1 or SMARCA4 protein expression has therapeutic significance, because this loss creates a dependence of the cancer cells on EZH2 activity. Preclinical studies have shown that some AT/RT xenograft lines with SMARCB1 loss respond to EZH2 inhibitors with tumor growth inhibition and occasional tumor regression.[23,24] In a study of the EZH2 inhibitor tazemetostat, objective responses were observed in adult patients whose tumors had either SMARCB1 or SMARCA4 loss (non-CNS malignant rhabdoid tumors and epithelioid sarcoma). (Refer to the Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section of this summary for more information.)
Rhabdoid Tumor Predisposition Syndrome (RTPS)
RTPS, which is primarily related to germline SMARCB1 alterations (and less commonly to germline SMARCA4 alterations), has been clearly defined.[9,20] RTPS is highly suggested in patients with synchronous occurrence of extracranial malignant rhabdoid tumor (kidney or soft tissue) and AT/RT, bilateral malignant rhabdoid tumors of the kidney, or malignant rhabdoid tumors in two or more siblings.
This syndrome is manifested by a marked predisposition to the development of malignant rhabdoid tumors in infancy and early childhood. Up to one-third of AT/RTs are thought to arise in the setting of RTPS, and most of these occur within the first year of life. The most common non-CNS malignancy of RTPS is malignant rhabdoid tumor of the kidney, which is also noted in infancy.
(Refer to the Genetic Testing and Surveillance of Rhabdoid Tumors of the Kidney section in the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information about RTPS.)
Cribriform Neuroepithelial Tumor
Cribriform neuroepithelial tumor is histologically and clinically distinct from AT/RT, but it has genomic and epigenomic characteristics that are very similar to AT/RT TYR. Like AT/RT, cribriform neuroepithelial tumor occurs in young children (median age, 1–2 years) and tumor cells lack SMARCB1 expression. Histologically, cribriform neuroepithelial tumor is characterized by the presence of cribriform strands and ribbons, but there is an absence of rhabdoid tumor cells with abundant eosinophilic cytoplasm. Like AT/RT TYR, tyrosinase expression is commonly observed. The outcome of patients with cribriform neuroepithelial tumor is more favorable than the outcome of patients with AT/RT TYR. In one study, only one death was reported among ten children with cribriform neuroepithelial tumor.
There is no defined staging system for childhood central nervous system atypical teratoid/rhabdoid tumor. For treatment purposes, patients are classified as having newly diagnosed or recurrent disease with or without neuraxis dissemination.
A standard treatment for children with newly diagnosed central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) has not yet been defined. Given the highly aggressive nature of the tumor, most patients have been treated with intensive multimodality therapy. However, the extent of treatment, particularly for radiation therapy, is limited because of the young age of most patients.
Treatment options for newly diagnosed CNS AT/RT include the following:
Surgery, Chemotherapy, and Radiation Therapy (Multimodality Therapy)
The extent of the surgical resection may affect survival. Data from the Central Nervous System Atypical Teratoid/Rhabdoid Tumor Registry (AT/RT Registry) suggest that patients who have had a complete resection may have a longer median survival, although complete surgical resection is often difficult because of the invasive nature of the tumor.
Chemotherapy has been the main adjuvant therapy for very young children with AT/RT. Cooperative group studies that included children younger than 36 months demonstrated poor survival when treated with standard chemotherapeutic regimens alone. The Children's Cancer Group reported a 2-year event-free survival (EFS) rate of 14% for 28 children younger than 36 months who were treated with multiagent chemotherapy.
Intensive regimens that use varying combinations of high-dose chemotherapy,[Level of evidence: 3iA]; [5,6][Level of evidence: 3iiiDi] intrathecal chemotherapy, and radiation therapy have led to prolonged survival for some patients.
Thirteen patients in the AT/RT Registry were treated with high-dose chemotherapy with hematopoietic stem cell rescue as part of initial therapy. Four of these patients, two of whom also received radiation, were alive without progressive disease 21.5 to 90 months after diagnosis at last report. Of 15 evaluable children (all younger than 32 months at diagnosis) who were on a chemotherapy Head Start III protocol, 2 survived for more than 47 months.[Level of evidence: 3iA]
Radiation therapy appears to have a positive impact on survival for patients with AT/RT.
Evidence (radiation therapy):
Evidence (multimodality therapy):
On the basis of the two prospective studies summarized above, multimodality therapy with surgery, radiation therapy, and chemotherapy seems to be the best treatment to optimize the survival of children with AT/RT. However, toxicities can be significant, and the most effective regimen and the optimal sequencing of therapies still need to be determined.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
There is no standard treatment for children with recurrent central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT).
Trials of molecularly targeted therapy are ongoing. In a study of the EZH2 inhibitor tazemetostat in adult patients with epithelioid sarcoma and non-CNS malignant rhabdoid tumors with SMARCB1 or SMARCA4 loss, prolonged stable disease and objective responses were observed. The activity of tazemetostat in children with AT/RT is under clinical evaluation.
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system atypical teratoid and rhabdoid tumor. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-cns-atrt-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389426]
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Last Revised: 2022-02-23
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