Atypical teratoid rhabdoid tumor pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Pathogenesis

• Atypical teratoid rhabdoid tumor is a primitive neuroectodermal tumor (PNET). The tumor cells are derived from the neuroectoderm, but have not developed and differentiated in the way a normal neuron would, and so the cells appear "primitive".
• Atypical teratoid rhabdoid tumor was until relatively recently classed as medulloblastoma, although both are clinically and histologically different.

Genetics

• Gene involved in the pathogenesis of atypical teratoid rhomboid tumor include SMARCB1 (hSNF5/INI-1), a tumor suppressor gene.
• Atypical teratoid rhabdoid tumor is characterized by loss of the long arm of chromosome 22, which results in loss of the hSNF5/INI-1 gene.
• INI1, a member of the SWI/SNF chromatin remodeling complex, is important in maintenance of the mitotic spindle and cell cycle control.

Genetic similarities have been found within rhabdoid tumors. In particular the chromosomal 22 deletion is very common in AT/RTs. The chromosome 22 area contains the hSNF5/INI1 gene that appears to function as a classic tumor suppressor gene. Most rhabdoid tumors have INI1 deletions whether they occur in the CNS, kidney or elsewhere. This mutation is viewed as the "first hit" which predisposes children to malignancies. INI1/hSNF5, a component of the chromatin remodeling SWI/SNF complex, is a critical tumor suppressor biallelically inactivated in rhabdoid tumors. Identification of INI1 as a tumor suppressor has facilitated accurate diagnosis of rhabdoid tumors.

The rate of transcription for SWI/SNF and HDAC complexes seem to be regulated by the INI1 gene. The SWI/SNF complex plays a role in chromatin remodeling. AT/RT is the first pediatric brain tumor for which a candidate tumor suppressor gene has been identified. A mutation or deletion in the INI1/hSNF5 gene occurs in the majority of AT/RT tumors. Up to 90% of AT/RT cases involve chromosome 22 deletion. This is mainly point mutations on the hSNF5/INI1 gene (i.e., one can diagnosis AT/RT without a chromsome 22 deletion elsewhere). The hSNF5/INI1 gene regulates 15 or so proteins in the chromintin structure. In addition, the OPN gene has a higher expression in AT/RT tumors. It is increasingly believed that the reason that all of the AT/RT cancers are not associated with the hSNF5/INI1 gene is that there are 14 additional proteins in the chromintin structure that are controlled by other genes. There are also some emerging mouse models of the AT/RT cancer as well as experimental cell lines derived from tumors. Despite these advances, the function of the gene is not yet understood. There is not enough known about the function of INI1, either as an independent modulator of gene expression or through its association with the SWI/SNF complex, to be able to use specific targeted biological agents for treatment. Prospective clinical and biologic trials are greatly needed to understand the efficacy of therapeutic interventions, as well as the role of the gene.

Gross Pathology

• Common intracranial sites associated with atypical teratoid rhabdoid tumor include:

Infratentorial	Supratentorial
Cerebellum Brain stem	Cerebral hemispheres Pineal gland Septum pellucidum Hypothalamus

Mircoscopic Pathology

AT/RT and rhabdoid tumor share the term "rhabdoid" because under a microscope both tumors resemble rhabdomyosarcoma. The tumor histology is jumbled small and large cells. The tissue of this tumor contains many different types of cells including the rhabdoid cells, large spindled cell, epithelial and mesencymal cells and areas resembling primitive neuroectodermal tumor (PNET). As much as 70% of the tumor may be made up of PNET-likw cells. Ultrastructure characteristic whorls of intermediate filaments in the rhabdoid tumors (as with rhabdoid tumors in any area of the body). Ho and associates found sickle shaped embracing cells, previously unreported, in all of 11 cases of AT/RT.

Associated Conditions

• Rhabdoid predisposition syndrome

Immunohistochemistry

Atypical teratoid rhabdoid tumor is demonstrated by positivity to tumor markers such as:

• Epithelial membrane antigen
• Vimentin
• Smooth muscle actin
• GFAP
• Cytokeratin
• Neurofilament
• Desmin