Purpose of This PDQ Summary
General Information
Background Information About Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

Incidence Clinical Behavior Presentation Prognosis

Cellular Classification and Tumor Biology of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

Diagnostic Evaluation of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

Stage Information
Treatment for Newly Diagnosed Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

Treatment Options Under Clinical Evaluation

Treatment for Recurrent Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor
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Changes to this summary (03/05/2009)
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Purpose of This PDQ 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/rhabdoid tumor. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Background.
• Cellular classification and tumor biology.
• Diagnostic evaluation.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. The PDQ childhood brain tumor treatment summaries are organized primarily according to the 2000 World Health Organization classification of nervous system tumors.[1]

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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. Refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview for information about the general classification of childhood brain and spinal cord tumors.

References

1. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000. 
   
   

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Background Information About Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

Incidence

The exact incidence of childhood central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is difficult to determine since the tumor has been widely recognized only for the last decade. In the Children’s Cancer Group study 9921, 10% of infants had AT/RT.[1] In Pediatric Oncology Group study 9233, 36 (11%) of 319 patients were identified in central review as having AT/RT. A Taiwanese study suggests an incidence of 26% in children aged younger than 3 years.[2] The incidence in older patients is unknown. In The AT/RT Registry, 12 of 42 patients (29%) were older than 36 months at the time of diagnosis.[3]

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.[4,5] In about half of patients, the tumor is located in the posterior fossa, although it can occur anywhere in the central nervous system.[1]

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 suggests that approximately 20% of patients present with disseminated disease.[3] 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.[6]

Most published information on outcome 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.[1,4,7] There are, however, reports of long-term survivors.[8]

References

1. Packer RJ, Biegel JA, Blaney S, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24 (5): 337-42, 2002 Jun-Jul.  [PUBMED Abstract]
   
   
2. Ho DM, Hsu CY, Wong TT, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: a comparative study with primitive neuroectodermal tumor/medulloblastoma. Acta Neuropathol 99 (5): 482-8, 2000.  [PUBMED Abstract]
   
   
3. Hilden JM, Meerbaum S, Burger P, et al.: Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22 (14): 2877-84, 2004.  [PUBMED Abstract]
   
   
4. Burger PC, Yu IT, Tihan T, et al.: 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 22 (9): 1083-92, 1998.  [PUBMED Abstract]
   
   
5. Lutterbach J, Liegibel J, Koch D, et al.: Atypical teratoid/rhabdoid tumors in adult patients: case report and review of the literature. J Neurooncol 52 (1): 49-56, 2001.  [PUBMED Abstract]
   
   
6. Biegel JA, Fogelgren B, Wainwright LM, et al.: Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 28 (1): 31-7, 2000.  [PUBMED Abstract]
   
   
7. Rorke LB, Packer RJ, Biegel JA: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85 (1): 56-65, 1996.  [PUBMED Abstract]
   
   
8. Olson TA, Bayar E, Kosnik E, et al.: Successful treatment of disseminated central nervous system malignant rhabdoid tumor. J Pediatr Hematol Oncol 17 (1): 71-5, 1995.  [PUBMED Abstract]
   
   

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Cellular Classification and Tumor Biology of Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

Childhood central nervous system atypical teratoid/rhabdoid tumor (AT/RT) was first described as a discrete clinical entity in 1987 [1] due to 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.[2]

Histologically, AT/RT contains sheets of rhabdoid cells against a background of primitive neuroectodermal cells, mesenchymal cells, or epithelial cells.[3] Immunohistochemical features help to identify the disease but vary depending on the cellular composition of the tumor. Rhabdoid cells express vimentin, epithelial membrane antigen, and smooth muscle actin. The primitive neuroectodermal cells variably express neurofilament protein, glial fibrillary acidic protein, keratin, or desmin. AT/RT is a rapidly growing tumor that can have an MIB-1 labeling index of 50% to 100%.[2]

AT/RT is the first primary pediatric brain tumor for which a candidate tumor suppressor gene, INI1, has been identified.[4] INI1 has been found to be abnormal in the majority of rhabdoid tumors, including central nervous system, renal, and extra renal rhabdoid malignancies.[4] In published series, 76% of AT/RTs had a deletion or mutation in INI1. INI1 is a component of a Switch (SWI) and Sucrose non-fermenting (SNF) ATP-dependent chromatin-remodeling complex.[5] The exact function of the INI1 gene is unknown but it is likely that a mutation results in altered transcriptional regulation of downstream targets. In addition to somatic mutations, germline mutations in INI1 have been reported in some AT/RT patients.[4,6] This appears to be more common in patients with rhabdoid tumors in two primary sites and germline screening may be an important predictor of risk to develop multiple primary tumors.

Immunohistochemical staining for INI1 has been developed and appears to be a useful tool in distinguishing AT/RT from primitive neuroectodermal tumors and other central nervous system tumors that can be confused with AT/RT.[7,8] It is now being used routinely to distinguish AT/RT from other brain tumors. This tool appears very helpful in identifying AT/RT even if the tumor does not have the classic morphologic features.

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. Treatment decisions are based on age of patient and extent of disease. The extent of disease affects long term outcome.

References

1. Rorke LB, Packer RJ, Biegel JA: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85 (1): 56-65, 1996.  [PUBMED Abstract]
   
   
2. Kleihues P, Louis DN, Scheithauer BW, et al.: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61 (3): 215-25; discussion 226-9, 2002.  [PUBMED Abstract]
   
   
3. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000. 
   
   
4. Biegel JA, Tan L, Zhang F, et al.: Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8 (11): 3461-7, 2002.  [PUBMED Abstract]
   
   
5. Biegel JA, Kalpana G, Knudsen ES, et al.: The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res 62 (1): 323-8, 2002.  [PUBMED Abstract]
   
   
6. Biegel JA, Fogelgren B, Wainwright LM, et al.: Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 28 (1): 31-7, 2000.  [PUBMED Abstract]
   
   
7. Judkins AR, Mauger J, Ht A, et al.: Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol 28 (5): 644-50, 2004.  [PUBMED Abstract]
   
   
8. Haberler C, Laggner U, Slavc I, et al.: Immunohistochemical analysis of INI1 protein in malignant pediatric CNS tumors: Lack of INI1 in atypical teratoid/rhabdoid tumors and in a fraction of primitive neuroectodermal tumors without rhabdoid phenotype. Am J Surg Pathol 30 (11): 1462-8, 2006.  [PUBMED Abstract]
   
   

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Stage Information

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 neuroaxis dissemination.

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Treatment for Newly Diagnosed Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor

There is no established standard treatment for children with central nervous system 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 suggests 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.[1] Chemotherapy has been the main adjuvant therapy for very young children with AT/RT. Cooperative group studies that included children aged younger than 36 months, demonstrated poor survival when treated with standard chemotherapeutic regimens alone.[2] 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.[3]

Intensive regimens that utilize varying combinations of high-dose chemotherapy, intrathecal chemotherapy, and radiation 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.[1] 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.[1] 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.[4] All but one surviving patient (seven of eight) in the older group received craniospinal irradiation and intensive chemotherapy with hematopoietic stem cell transplant; only three of 22 of the younger patients received any form of radiation therapy, two of whom are disease-free.

Another therapeutic approach to patients with AT/RT is based on the Third Intergroup Rhabdomyosarcoma (IRS-III) Study. It utilizes radiation therapy, intrathecal methotrexate, cytarabine, hydrocortisone, and systemic multiagent chemotherapy. Three patients all showed responses to therapy and one had prolonged survival.[5] More recently another group reported success in four patients with AT/RT using IRS-III-like therapy; a prospective study using this treatment is being conducted.[6] Prospective cooperative group clinical trials for AT/RT are greatly needed to better understand how age and extent of therapy impact survival.

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.

• The Children’s Oncology Group has developed a phase III study (ACNS0333) 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.

References

1. Hilden JM, Meerbaum S, Burger P, et al.: Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22 (14): 2877-84, 2004.  [PUBMED Abstract]
   
   
2. Packer RJ, Biegel JA, Blaney S, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24 (5): 337-42, 2002 Jun-Jul.  [PUBMED Abstract]
   
   
3. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005.  [PUBMED Abstract]
   
   
4. Tekautz TM, Fuller CE, Blaney S, et al.: 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 23 (7): 1491-9, 2005.  [PUBMED Abstract]
   
   
5. Olson TA, Bayar E, Kosnik E, et al.: Successful treatment of disseminated central nervous system malignant rhabdoid tumor. J Pediatr Hematol Oncol 17 (1): 71-5, 1995.  [PUBMED Abstract]
   
   
6. Zimmerman MA, Goumnerova LC, Proctor M, et al.: Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor. J Neurooncol 72 (1): 77-84, 2005.  [PUBMED Abstract]
   
   

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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.

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Changes to this summary (03/05/2009)

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.

Stage Information

Added text to state that patients are classified as having disease with or without neuroaxis dissemination.

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