MTAP and p16 as immunohistochemical surrogates of CDKN2A/B homozygous deletion in central nervous system tumors: A multicentre Italian experience

Objective: To evaluate the diagnostic performance of MTAP and p16 immunohistochemistry (IHC) as surrogate markers for CDKN2A/B homozygous deletion (HD) in central nervous system (CNS) tumors, and to assess their prognostic significance. Methods: Molecular tests including gene sequencing or fluorescence in situ hybridization (FISH) have traditionally been used to assess CDKN2A/B HD. However, due to lower costs and wider availability, IHC surrogates such as MTAP and p16 are gaining interest. We investigated the concordance between MTAP and p16 IHC expression and CDKN2A/B status as determined by FISH. Results: Our cohort consisted of 227 patients with various CNS tumor types: glioblastoma IDH-wild type (n = 64; 28.2 %), meningioma (n = 61; 26.9 %), IDH-mutant astrocytoma (n = 52; 22.9 %), IDH-mutant and 1p/19q-codeleted oligodendroglioma (n = 35; 15.4 %), and pleomorphic xanthoastrocytoma (n = 15; 6.6 %). In all tumor types, most cases with CDKN2A/B HD showed MTAP loss and p16 negativity (p-values < 0.05). The combination of MTAP and p16 IHC yielded a sensitivity of 92 %, specificity of 80 %, positive predictive value of 86 %, and negative predictive value of 88 % in detecting CDKN2A/B HD. Survival analysis demonstrated significantly reduced disease-free and overall survival among patients with MTAP loss, p16 negativity, and CDKN2A/B HD. Conclusions: MTAP immunohistochemistry, alone or combined with p16, represents a cost-effective and feasible surrogate for detecting CDKN2A/B homozygous deletion in CNS tumors and provides relevant prognostic information.