Diagnostic Evaluation 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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