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.   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 full 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.
Central nervous system (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. About 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, a tumor suppressor gene. There is no current standard treatment for children with AT/RT. Multimodal treatment consisting of surgery, chemotherapy, and radiation therapy is under evaluation.
Based on present biologic 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 cancer therapy side effects 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 has been widely recognized for only the last decade.
The incidence in older patients is unknown. However, in the Central Nervous System Atypical Teratoid/Rhabdoid Tumor Registry (AT/RT Registry), 12 (29%) of the 42 patients 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.
Childhood AT/RT is a clinically aggressive tumor that primarily occurs in children younger than 3 years, but it also can occur in older children and has been reported in adults.  
In about one-half of patients, the tumor is located in the posterior fossa, although it can occur anywhere in the CNS.  Tumors of the posterior fossa may occur in the cerebellopontine angle or more midline. Involvement of individual cranial nerves has also 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 are dependent on tumor location. Young patients with posterior fossa tumors usually present with symptoms related to hydrocephalus, including the following:
They may also develop ataxia or regression of motor skills.
Data from the AT/RT Registry suggest that approximately 20% of patients present with disseminated disease.  Dissemination is typically through leptomeningeal pathways seeding the spine and other areas of the brain. There are also reports of rare patients with synchronous renal rhabdoid tumor and CNS AT/RT. 
All patients with suspected childhood AT/RT should have MRI of the brain and spine. Unless medically contraindicated, patients should also have lumbar cerebrospinal fluid inspected for evidence of tumor. Patients may also undergo renal ultrasound to detect synchronous tumors.
AT/RT cannot be reliably distinguished from other malignant brain tumors based on clinical history or radiographic evaluation. Surgery is necessary to obtain tissue and confirm the diagnosis of AT/RT. Immunostaining for loss of SMARCB1 (INI1, hSNF5) protein expression is used to confirm the diagnosis, especially in children younger than 3 years. 
Prognostic factors that affect survival for AT/RTs are not fully delineated.
Known factors associated with a poor outcome include the following:
Most published information on outcomes for patients with AT/RT is based on small series and is retrospective in nature. Initial retrospective studies reported an average survival from diagnosis of only about 12 months.      In a retrospective report, 2-year overall survival 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. 
There are reports of long-term survivors.  Notably, improved survival has been reported for those receiving intensive multimodal therapy.
Childhood central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) was first described as a discrete clinical entity in 1987  based on its distinctive pathologic and genetic characteristics. Before then, it was most often classified as a medulloblastoma, primitive neuroectodermal tumor, or choroid plexus carcinoma. The World Health Organization (WHO) began classifying AT/RT as an embryonal grade IV neoplasm in 1993. 
Histologically, classic 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.
Immunohistochemistry 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).   
AT/RT is a rapidly growing tumor that can have an MIB-1 labeling index of 50% to 100%. 
AT/RT was the first primary pediatric brain tumor for which a candidate tumor suppressor gene, SMARCB1 (also known as INI1 and hSNF5), was identified.  SMARCB1 is genomically altered in the majority of rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.  Additional genomic alterations (mutations and gains/losses) in other genes are very uncommon in patients with SMARCB1-associated AT/RT, and there are no other genes that are recurrently mutated.   
SMARCB1 is a component of a switch (SWI) and sucrose non-fermenting (SNF) adenosine triphosphate–dependent chromatin-remodeling complex.  Rare familial cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 mutations have also been associated with germline mutations of SMARCA4/BRG1, another member of the SWI/SNF chromatin-remodeling complex.  
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, more rarely, other SWI/SNF complex members), biologically distinctive subsets of AT/RT have been identified.   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: 
In addition to somatic mutations, germline mutations in SMARCB1 have been reported in a substantial subset of AT/RT patients.   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 multiple 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.   Screening children diagnosed with AT/RT for germline SMARCB1 mutations may provide useful information for counseling families on the genetic implications of their child’s AT/RT diagnosis. 
RTPS, related primarily to germline SMARCB1 alterations, has been clearly defined.   RTPS is highly suggested in patients with synchronous occurrence of renal malignant rhabdoid tumor 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 the majority of these occur within the first year of life. The most common non-CNS malignancy of RTPS is the malignant rhabdoid tumor of the kidney, which is also noted in infancy.
For more information about RTPS, refer to the Rhabdoid predisposition syndrome section in the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment.
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 for patients with cribriform neuroepithelial tumor is more favorable than the outcome for patients with AT/RT TYR, with only one death 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.
There is no established standard treatment for children with central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT). Given the highly aggressive nature of the tumor, most patients have been treated with intensive multimodal therapy. However, the young age of most patients limits the extent of treatment, particularly radiation therapy.
Treatment options for newly diagnosed CNS AT/RT include the following:
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 given 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) of 14% for 28 children younger than 36 months treated with multiagent chemotherapy. 
Intensive regimens that utilize varying combinations of high-dose chemotherapy, [Level of evidence: 3iA];  [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 AT/RT patients.
Evidence (multimodal therapy):
Because AT/RT is responsive to radiation therapy, this modality is incorporated into many treatment protocols. 
Prospective cooperative group clinical trials for AT/RT are greatly needed to better understand how age and extent of therapy affect survival.
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 recurrent childhood central nervous system atypical teratoid/rhabdoid tumor (AT/RT).
In a report of four children with recurrent AT/RT treated with an aurora kinase inhibitor, three children responded; the responses were sustained for more than 1 year.  A larger trial (NCT02114229) is underway.
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:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
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.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Tumor Biology of Childhood Central Nervous System (CNS) Atypical Teratoid/Rhabdoid Tumor (AT/RT)
Added Cribriform Neuroepithelial Tumor as a new subsection.
Treatment of Newly Diagnosed Childhood CNS AT/RT
Added text to state that a report using the National Cancer Database described the outcome of 361 children with CNS AT/RT who were aged 0 to 18 years at diagnosis and treated in two periods. The report confirmed the increased use of trimodal therapy during the study period and an improvement in outcome (cited Fischer-Valuck et al. as reference 13).
Treatment of Recurrent Childhood CNS AT/RT
Added text to state that in a report of four children with recurrent AT/RT treated with an aurora kinase inhibitor, three children responded; the responses were sustained for more than 1 year (cited Wetmore et al. as reference 1). Also added text to state that a larger trial (NCT02114229) is underway.
Added text about the NCT02114229 trial as a treatment option under clinical evaluation for recurrent childhood CNS AT/RT.
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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 who care for cancer 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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Date first published: 2008-12-22 Date last modified: 2018-01-24
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