Characterization of Switch/Sucrose Nonfermenting Complex Proteins and Nestin Expression in a Cohort of Pediatric Central Nervous System Tumors

Abstract

Tumors of the central nervous system (CNS) in pediatric patients have undergone significant diagnostic refinement through the use of immunohistochemistry (IHC) and molecular techniques. The utility of these novel IHC antibodies has been demonstrated with the inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in the diagnosis of atypical teratoid/rhabdoid tumors, predominantly through the loss of integrase interactor 1 (INI1; SMARCB1). Alternatively, these tumors may have inactivation of brahma-related gene 1 (BRG1; SMARCA4) in a subset of cases. The role of other SWI/SNF component proteins and their expression in pediatric brain tumors is not well established. Nestin, an intermediate filament, has been shown to be present in some pediatric CNS tumors, but of uncertain diagnostic and prognostic significance. We sought to explore the immunohistochemical expression profile for common SWI/SNF subunits and nestin in a pediatric CNS tumor cohort. Using a 118-sample tissue microarray, we performed IHC for INI1, BRG1, brahma (BRM), ARID1A, ARID1B, polybromo 1, and nestin. In 19 cases, INI1 was lost and BRG1 was lost in 2 cases. Interestingly, 6 cases originally diagnosed as primitive neuroectodermal tumors showed isolated loss of BRM. Other SWI/SNF proteins did not provide further diagnostic resolution. Nestin was positive in 76.2% of INI1/BRG1-deficient tumors, compared with 29.1% in INI1/BRG1-intact tumors yielding a sensitivity of 76.2%, specificity of 68.0%, and a P value of <0.001, but nestin positivity did not correlate specifically with poor outcomes. In conclusion, we confirm the utility of BRG1 IHC in the workup of pediatric CNS tumors, which may facilitate a difficult diagnosis when conventional markers are inconclusive, or as a first-line marker in cases where intraoperative smears are suggestive of atypical teratoid/rhabdoid tumor. Although nestin expression was associated with SWI/SNF inactivation, it did not yield statistically significant diagnostic or prognostic information in our study. Interestingly, we identified 6 tumors with isolated BRM IHC loss, the significance of which is uncertain but warrants further investigation.