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Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment (PDQ®)

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Tumor Biology of Childhood CNS 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 [1] 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 began classifying AT/RT as an embryonal grade IV neoplasm in 1993.[2]

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.[3]

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.[4] 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).[5-7]

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, SMARCB1 (also known as INI1 and hSNF5), has been identified.[8] SMARCB1 loss causes aberrant activation of the sonic hedgehog pathway and may drive tumorigenesis through the expression of GLI1.[9] In one series of six infants, AT/RTs were thought to arise from the superior medullary velum. Sonic hedgehog signaling through expression of GLI1 is critically involved in morphogenesis of the cerebellar midline structures, suggesting, in part, why tumors arise in this region.[10] SMARCB1 has been found to be abnormal in the majority of rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.[8] Alterations (mutations as well as gains/losses) in other genes are very uncommon in patients with SMARCB1-associated AT/RT.[11-13]

SMARCB1 is a component of a Switch (SWI) and Sucrose non-fermenting (SNF) adenosine triphosphate–dependent chromatin-remodeling complex.[14] 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.[7,15]

In addition to somatic mutations, germline mutations in SMARCB1 have been reported in a substantial subset of AT/RT patients.[8,16] A study of 65 children with rhabdoid tumors found that 23 (35%) had germline mutations and/or deletions of SMARCB1.[5] 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.[5] 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.[5] 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 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.[5]

Rhabdoid Tumor Predisposition Syndrome (RTPS)

RTPS, related primarily to germline SMARCB1 alterations, has been clearly defined.[8,16] 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.


  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. McLendon RE, Adekunle A, Rajaram V, et al.: Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study. Arch Pathol Lab Med 135 (8): 984-93, 2011. [PUBMED Abstract]
  5. Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011. [PUBMED Abstract]
  6. Bruggers CS, Bleyl SB, Pysher T, et al.: Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatr Blood Cancer 56 (7): 1026-31, 2011. [PUBMED Abstract]
  7. Hasselblatt M, Gesk S, Oyen F, et al.: Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 35 (6): 933-5, 2011. [PUBMED Abstract]
  8. 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]
  9. Jagani Z, Mora-Blanco EL, Sansam CG, et al.: Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 16 (12): 1429-33, 2010. [PUBMED Abstract]
  10. Tomita T, Frassanito P: Tumors of the superior medullary velum in infancy and childhood: report of 6 cases. J Neurosurg Pediatr 11 (1): 52-9, 2013. [PUBMED Abstract]
  11. Lee RS, Stewart C, Carter SL, et al.: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122 (8): 2983-8, 2012. [PUBMED Abstract]
  12. Kieran MW, Roberts CW, Chi SN, et al.: Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 59 (7): 1155-7, 2012. [PUBMED Abstract]
  13. Hasselblatt M, Isken S, Linge A, et al.: High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosomes Cancer 52 (2): 185-90, 2013. [PUBMED Abstract]
  14. 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]
  15. Schneppenheim R, Frühwald MC, Gesk S, et al.: Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86 (2): 279-84, 2010. [PUBMED Abstract]
  16. 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]
  • Updated: September 5, 2014