- General Information
- Background Information About Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
- Cellular Classification and Tumor Biology of Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
- Stage Information
- Treatment for Newly Diagnosed Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
- Treatment for Recurrent Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
- Changes to This Summary (04 / 02 / 2013)
- About This PDQ Summary
- Get More Information From NCI
Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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Childhood Atypical Teratoid/Rhabdoid Tumor Treatment
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization classification of nervous system tumors.[1,2] 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up 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.)
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Background Information About Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
Based on present biologic understanding, atypical teratoid/rhabdoid tumor (AT/RT) is part of a larger family of rhabdoid tumors. In this summary, AT/RT refers to central nervous system (CNS) tumors only and rhabdoid tumor reflects the possibility of both CNS and non-CNS tumors. Unless noted otherwise in the text, this summary is referring to AT/RT.
The exact incidence of childhood CNS AT/RT is difficult to determine because the tumor has been widely recognized only for the last decade. In two recent North American based prospective studies performed by the Children's Cancer Group and the Pediatric Oncology Group for children aged 3 years or younger at diagnosis, retrospective review disclosed that approximately 10% of children had AT/RTs. A Taiwanese study found that AT/RTs account for 26% of primitive or embryonal tumors in children younger than 3 years. The Austrian Brain Tumor Registry, conducted between 1996 and 2006, confirmed that AT/RTs represent the sixth most common malignant brain tumor in 311 newly diagnosed children (6.1%), with a peak incidence during the first 2 years of life. The incidence in older patients is unknown. In the Central Nervous System Atypical Teratoid/Rhabdoid Tumor Registry (AT/RT Registry), 12 of 42 patients (29%) were older than 36 months at the time of diagnosis.
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.[5,6] In about one-half of patients, the tumor is located in the posterior fossa, although it can occur anywhere in the CNS.
Signs and symptoms related to the tumor are dependent on location. Young patients with posterior fossa tumors usually present with symptoms related to hydrocephalus such as early morning headaches, vomiting, and lethargy. They may also develop ataxia or regression of motor skills. Because AT/RT grows rapidly, patients typically have a fairly short history of progressive symptoms measured in days to weeks. 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 and AT/RT.
Prognostic factors that affect survival for AT/RTs are not fully delineated. Factors associated with a poor outcome include the following:
- Germline mutation.
- Age younger than 2 years.
- Metastases at diagnosis.
- Subtotal resection.
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.[1,5,10,11,12] In another retrospective report, 2-year overall survival was better for patients who underwent a gross-total resection than for those who had a subtotal tumor removal. However, the contribution of radiation therapy was less clear. There are, however, reports of long-term survivors. Notably, improved survival has been reported for those aged 3 years and older who received postoperative craniospinal irradiation and high-dose alkylator-based chemotherapy compared with those younger than 3 years with AT/RT. In this report, the incidence of leptomeningeal metastases was also higher in the infant group of patients. In one prospective study of 25 children with AT/RT receiving intensive multimodal therapy, including radiation and intrathecal chemotherapy, the reported 2-year progression-free survival rate was 53%, and the overall survival rate was 70%.
Cellular Classification and Tumor Biology of Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
Childhood central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) was first described as a discrete clinical entity in 1987  because of its pathologic and genetic characteristics. Prior to that, it was often misclassified as a medulloblastoma, primitive neuroectodermal tumor, or choroid plexus carcinoma. The World Health Organization began classifying it as an embryonal grade IV neoplasm in 1993.
AT/RT is a rapidly growing tumor that can have an MIB-1 labeling index of 50% to 100%. Immunohistochemistry for INI1 protein is useful in establishing the diagnosis of AT/RT. A loss of INI1 staining is noted in neoplastic cells, but staining is retained in non-neoplastic cells (e.g., vascular endothelial cells).[3,4,5]
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.
AT/RT is the first primary pediatric brain tumor for which a candidate tumor suppressor gene, SMARCB1 (also known as INI1 and hSNF5), has been identified.SMARCB1 has been found to be abnormal in the majority of rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies. Alterations (mutations as well as gains/losses) in other genes are very uncommon in patients with SMARCB1-associated AT/RT.[9,10,11]SMARCB1 is a component of a Switch (SWI) and Sucrose non-fermenting (SNF) adenosine triphosphate-dependent chromatin-remodeling complex. The exact function of the SMARCB1 gene is unknown, but it is likely that a mutation results in altered transcriptional regulation of downstream targets. 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.[5,13]
In addition to somatic mutations, germline mutations in SMARCB1 have been reported in some AT/RT patients.[8,14] 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 sporadic cases (median age, approximately 5 months versus 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.[3,4] 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.
Diagnostic Evaluation of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor
All patients with childhood AT/RT should have magnetic resonance imaging of the brain and spine at the time of diagnosis. Unless medically contraindicated, patients should also have lumbar cerebrospinal fluid inspected for evidence of tumor. Consideration should also be given to renal ultrasound to detect synchronous tumors. There is no way to reliably distinguish AT/RT from other malignant brain tumors based on clinical history or radiographic evaluation. Embryonal tumors, especially in those younger than 3 years, should undergo immunostaining for loss of SMARCB1 (INI1, hSNF5) protein expression to confirm the diagnosis.
A Rhabdoid Tumor Predisposition Syndrome (RTPS), related primarily to germline SMARCB1 alterations, has been clearly defined.[8,14] 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. 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.
There is no defined staging system for childhood central nervous system atypical teratoid/rhabdoid tumor (AT/RT). Patients are classified as having newly diagnosed or recurrent disease with or without neuraxis dissemination.
Treatment for Newly Diagnosed Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
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. The young age of the majority of patients does, however, put some limitations on the extent of treatment, particularly radiation. Surgery is necessary to obtain tissue and make the diagnosis of AT/RT. Data from the 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]; [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 following diagnosis at last report. Radiation therapy appears to have an impact on survival for AT/RT patients. Of the 42 patients in the AT/RT Registry, 13 patients (31%) received radiation therapy in addition to chemotherapy as part of their primary therapy. The radiation field was to the primary tumor bed in nine children, and the tumor bed and the craniospinal axis in four children. Their median survival was 48 months, while the median survival of all patients on the registry was 16.75 months. Supporting the value of radiation therapy was a retrospective series of 31 patients with AT/RT from St. Jude Children's Research Hospital in which the 2-year EFS for patients older than 3 years was 78%, considerably better than 11% for patients younger than 3 years. All but one of the surviving patients (seven of eight) in the older group received craniospinal irradiation and intensive chemotherapy with hematopoietic stem cell transplant; only 3 of 22 of the younger patients received any form of radiation therapy, two of whom are disease free. In a Surveillance, Epidemiology, and End Results registry review, radiation therapy was associated with improved survival in children younger than 3 years.
Another therapeutic approach to treating patients with AT/RT is based on the Third Intergroup Rhabdomyosarcoma (IRS-III) Study. It utilized radiation therapy, intrathecal methotrexate, cytarabine, hydrocortisone, and systemic multiagent chemotherapy. The results of small retrospective series were encouraging,[9,10] leading to the first prospective study of multimodality treatment in this group of patients. Results of the prospective study demonstrated a 2-year progression-free survival of 53% ± 13% and an overall survival of 70% ± 10%, with results most favorable in children who were older, had a gross total resection, and had no metastatic disease at presentation. Prospective cooperative group clinical trials for AT/RT are greatly needed to better understand how age and extent of therapy affect survival.
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ACNS0333 (Combination Chemotherapy, Radiation Therapy, and an Autologous Peripheral Blood Stem Cell Transplant in Treating Young Patients With AT/RT of the CNS): The Children's Oncology Group has developed a phase III study for patients aged 0 to 21 years with AT/RT. The study uses multiagent chemotherapy, radiation, and high-dose chemotherapy with hematopoietic stem cell rescue.
Treatment for Recurrent Childhood Central Nervous System Atypical Teratoid / Rhabdoid Tumor
There is no standard treatment for recurrent childhood central nervous system atypical teratoid/rhabdoid tumor. Entry into studies of novel therapeutic approaches should be considered. Information about ongoing clinical trials is available from the NCI Web site.
Treatment Options Under Clinical Evaluation
Early-phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities.
Changes to This Summary (04 / 02 / 2013)
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.
Cellular Classification and Tumor Biology of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor
Added text to state that alterations in other genes are very uncommon in patients with SMARCB1-associated atypical teratoid/rhabdoid tumor (cited Lee et al., Kieran et al., and Hasselblatt et al. as references 9, 10, and 11, respectively).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
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 who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment are:
- Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
- Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Roger J. Packer, MD (Children's National Medical Center)
- Malcolm A. Smith, MD, PhD (National Cancer Institute)
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Levels of Evidence
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Last Revised: 2013-04-02
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