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P10.26.a an Evaluation of the Diagnostic Accuracy of a Minimal Immunohistochemical Panel for Atypical Teratoid/rhabdoid Tumor (at/rt) Molecular Subtyping, Benchmarked Against Dna Methylation Profiling

Year: 2025
Type: conference-abstract
Abstract: BACKGROUND AT/RT are aggressive pediatric central nervous system (CNS) malignancies, characterized by biallelic inactivation of either SMARCB1 (95%) or SMARCA4 (5%). Transcriptomic and DNA methylation analyses classify AT/RT into three molecular subgroups: SHH (marked by neurogenesis and NOTCH pathway gene expression, e.g., ASCL1), TYR (expressing melanosomal markers such as TYR, MITF and OTX2), and MYC (overexpressing MYC and HOXC clusters). Given that they can differ in tumor location, age of onset, and possibly overall survival rates, molecular classification of ATRT is anticipated to impact clinical decision-making. However, due to availability and financial constraints, resource limited institutes are unable to use DNA methylation profiling as a first-line approach and hence immunohistochemical (IHC) surrogates are needed. MATERIAL AND METHODS We analysed a case series of 10 pediatric AT/RTs—nine SMARCB1-deficient and one SMARCA4-deficient—to evaluate the sensitivity and specificity of an IHC marker panel (3 antibodies; Tyrosinase, SOX11 and MYC) and its concordance with DNA-methylation profiling in predicting molecular subgroups. RESULTS In this study, 9 out of 10 cases were consistently assigned to a specific AT/RT molecular subgroup with high confidence (calibrated score ≥ 0.9), including 4 MYC, 2 SHH, and 3 TYR subtypes based on methylation profiling. The remaining one case was ambiguously classified as either AT/RT-TYR or cribriform neuroepithelial tumor with SMARCB1 alteration, with a low calibrated score. As a result, 9 well-defined AT/RT cases were included for comparison with IHC subtyping. Among these, the concordance between IHC and DNA methylation profiling was nearly perfect, with a κ coefficient of 0.90 and only one discrepant case. Specifically, there was 100% agreement for the TYR and SHH subgroups. The discrepant case classified as AT/RT-MYC on methylation showed SOX11 immunoexpression, supporting the notion that MYC IHC should be negative when SOX11 is positive, to favor an AT/RT-SHH diagnosis. Thus high sensitivity and specificity of the IHC markers, along with the strong concordance between IHC and DNA methylation profiling, highlight the reliability of this method for accurately identifying AT/RT molecular subtypes. CONCLUSION Though our study is limited by small number of cases, however we suggest that incorporating MYC, SOX11, and Tyrosinase into immunohistochemical panels for subtyping, and including them in future clinical trials, may help elucidate their clinicopathological significance and further establish their utility as surrogate markers for AT/RT molecular subgroups, particularly in resource-limited settings.
DOI: 10.1093/neuonc/noaf193.337
Language: English
Open Access status: bronze
OpenAlex ID: W4414786608
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