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Atypical Teratoid Rhabdoid Tumor (AT/RT)

Kar-Ming Fung, M.D., Ph.D.¹ and Gregory N. Fuller, M.D., Ph.D.²

¹ Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
² Department of Anatomic Pathology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Last update: July 21, 2006

Summary: A highly malignant pediatric embryonal tumor of the CNS (WHO grade IV) that exhibits rhabdoid neoplastic cells with or without non-rhabdoid components. A medulloblastoma-like and/or a primitive neuroectodermal tumor (PNET)-like component are the most common non-rhabdoid elements. A carcinomatous component or a sarcomatous component can also be present in some cases. Most AT/RT are associated with a deletion or mutation of the INI1/hSNF5/SMARCB1/BAF47 gene on chromosome 22q11.2.

Behavior: Grave prognosis with a median survival of 6 months. Patients older than three yearsold may have a slightly better prognosis (Tekautz TM et al., 2005). One third of patients have widespread metastases throughout the cerebrospinal pathways at presentation.

Age: Most cases arise before 2 years of age. Less common in older children. Rare examples have been reported in adults.

Incidence: Uncommon but not rare. Less frequently seen than medulloblastoma.

Location: Most commonly seen in the posterior fossa (cerebellum and cerebellopontine angle). Can also be seen in the cerebral hemispheres. Uncommon, but well documented, in other sites, including the pineal gland, brainstem, and spinal cord.

Association: Associated with rhabdoid predisposition syndrome (Sevenet N et al., 1999).

Genetics and Molecular Pathology: Deletion, homozygous or heterozygous, of chromosome 22q11.2 and mutation of the hSNF5/INI1 gene have been demonstrated in most cases (Bruch LA et al., 2001, Biegel JA et al., 2002). Lack of expression of the product of the hSNF5/INI1 gene can be detected by immunohistochemistry using the monoclonal antibody BAF 47 (Judkins AR et al., 2004).

Clinical Features: The symptoms are similar to other rapidly-growing tumors. Hydrocephalus with head enalargement can be seen as AT/RT occurs most commonly in infants.

Imaging Features: MR imaging usually demonstrates a mass with increased intensity on T2-weighted images and nonhomogeneous contrast enhancement on T1-post gadolinium sequences (Parmar H et al., 2006; Cheng YC et al., 2005). Cyst formation and hemorrhage are not uncommon.

Gross Pathology: MR imaging usually demonstrates a mass with increased intensity on T2-weighted images and nonhomogeneous contrast enhancement on T1-post gadolinium sequences (Parmar H et al., 2006; Cheng YC et al., 2005). Cyst formation and hemorrhage are not uncommon.

Histology: (Rorke LB et al., 1996)

Rhabdoid Cells: The salient histologic feature is the presence of rhabdoid cells. Rhabdoid cells are medium-to-large, round-to-oval cells with distinct cell borders and an eccentric, enlarged nucleus with a prominent nucleolus. The cytoplasm has a finely granular, homogenous character. Multinuclearted tumor cells are not uncommon. The center of the cell typically contains a poorly defined, dense, pink, hyalinized inclusion body that displaces the nucleus to the periphery .
Non-Rhabdoid component: AT/RTs composed purely of rhabdoid cells are less common than those that also exhibit a non-rhabdoid component. A medulloblastoma-like or PNET-like component are the most common. Malignant epithelial (carcinomatous) and mesenchymal (sarcomatous) components may also be seen, but are less frequently seen.
Percentage of rhabdoid cell component: This is quite variable from tumor to tumor, and also in different parts of the same tumor. When rhabdoid cells are not abundant, they may have to be diligently searched for. This may be particularly difficult on frozen sections.
Intraoperative cytologic preparation: This is a very good tool for identifying rhabdoid cells during intraoperative frozen section consultation.

Immunohistochemistry:

Negative for skeletal muscle markers: AT/RTs are negative for phenotypic markers specific for skeletal muscle differentiation, including MyoD and desmin.
Vimentin: The rhabdoid cells are strongly and diffusely positive for vimentin. The rhabdoid features are particularly well demonstrated by immunohistochemistry for vimentin, which is a helpful mean to identify these cells in cases when they are not abundant.
Polyphenotypic: AT/RTs are typically polyphenotypic and usually show reactivity for other antigens, including glial fibrillary acidic protein, neurofilament proteins, smooth muscle actin, S-100, cytokeratin, and CD99.
INI1 gene product (BAF 47): As mentioned previously, they are negative for the hSNF5/INI1 gene product, as demonstrated by the commercially available BAF47 antibody. Endothelial cells, reactive chronic inflammatory cell infiltrates and other endogenous cellular constituents provide an internal positive control for the antibody.

Electron Microscopy: The eosinophilic hyalinized cytoplasmic inclusion body seen on H&E-stained tissue sections typically appears as a dense deposit of intermediate filaments at the ultrastructural level.

Differential Diagnosis: In classical cases that display typical histopathologic features and arise in an appropriate clinical setting, the diagnosis of AT/RT is relatively straight forward. When there is doubt, immunohistochemistry using the BAF 47 antibody (Judkins AR et al., 2004) or detection of chromosome 22q11.2 deletion by fluorescent in situ hybridization are useful confirmatory adjuncts (Bruch LA et al., 2001).

Primary and metastatic rhabdomyosarcoma: Primary rhabdomyosarcoma of the CNS is extremely rare but does occur. Metastatic rhabdomyosarcoma is far more common. A positive clinical history is extremely helpful. AT/RTs are negative for MyoD and desmin; rhabdomyosarcomas are positive for the these markers.
Metastatic rhabdoid tumor: Rhabdoid tumors can arise during infancy in the kidney or soft tissues. A thorough clinical history is important in ruling out these possibilities.
Medulloblastoma and PNETs: In AT/RTs that display a substantial small cell component and scant rhabdoid component, a careful search for rhabdoid cells is critical for correct diagnosis. In addition, in contrast to AT/RTs, medulloblastomas retain expression of INI1.
Choroid plexus carcinoma: Choroid plexus carcinoma (CPC): AT/RT and choroid plexus carcinoma share several overlapping clinical and histopathological features. The separation of these two entities may not be clear in some cases. Furthermore, mutation of INI1 has been reported in some CPCs. A recent study of 28 tumors carrying a diagnosis of CPC found retained expression of INI1 in 21 of 28 (75%) of the tumors (Judkins AR et al., 2005). The remaining 7 cases (25%) that were immunonegative for INI1 exhibited features compatible with ATRT. It is likely that INI1 expression is a better separator of CPC from ATRT, with the attendant implications for more aggressive clinical behavior for AT/RT, compared to histology, ultrastructure, routine immunophenotype or cytogenetic analysis alone.
Composite rhabdoid tumors: A number of different types of neoplasms that are encountered within the central nervous system can exhibit a prominent or even predominant rhabdoid phenotype, including meningioma, glioblastoma, metastatic carcinoma, metastatic melanoma, and various primary, secondary (radiation-associated) and metastatic sarcomas. In addition to imaging studies, immunophenotype and clinical history, all of these composite tumors can be distinguished from AT/RT by their retained expression (immunopositivity) of INI1 (Perry A et al., 2005).
Other tumors that do not express INI1/hSNF5/SMARCB1/BAF47: A recent survey of a wide variety of CNS and systemic tumor types found that rhabdoid tumors, epithelioid sarcomas and renal medullary carcinoma did not express INI1/hSNF5/SMARCB1/BAF47 by immunohistochemistry; all other tumor types retained expression of this marker (Sigauke E et al., 2006).

Reference:

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Bruch LA, Hill DA, Cai DX, Levy BK, Dehner LP, Perry A. A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumors. Hum Pathol 2001 Feb;32(2):156-62.
Cheng YC, Lirng JF, Chang FC, Guo WY, Teng MM, Chang CY, Wong TT, Ho DM. Neuroradiological findings in atypical teratoid/rhabdoid tumor of the central nervous system. Acta Radiol. 2005 Feb;46(1):89-96.
Judkins AR, Burger PC, Hamilton RL, Kleinschmidt-DeMasters B, Perry A, Pomeroy SL, Rosenblum MK, Yachnis AT, Zhou H, Rorke LB, Biegel JA. INI1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma. J Neuropathol Exp Neurol 2005 May;64(5):391-7.
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Perry A, Fuller CE, Judkins AR, Dehner LP, Biegel JA. INI1 expression is retained in composite rhabdoid tumors, including rhabdoid meningiomas. Mod Pathol. 2005 Jul;18(7):951-8.
Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996 Jul;85(1):56-65.
Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet. 1999 Nov;65(5):1342-8.
Sigauke E, Rakheja D, Maddox DL, Hladik CL, White CL, Timmons CF, Raisanen J. Absence of expression of SMARCB1/INI1 in malignant rhabdoid tumors of the central nervous system, kidneys and soft tissue: an immunohistochemical study with implications for diagnosis. Mod Pathol. 2006 May;19(5):717-25.
Tekautz TM, Fuller CE, Blaney S, Fouladi M, Broniscer A, Merchant TE, Krasin M, Dalton J, Hale G, Kun LE, Wallace D, Gilbertson RJ, Gajjar A. Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. Clin Oncol. 2005 Mar 1;23(7):1491-9.