Role of Surrogate Immunohistochemistry Markers in CNS Tumors in the Era of Molecular Diagnostics With Recent Updates

Molecular profiling is becoming crucial for accurate classification, prognostication, and therapeutic stratification for central nervous system (CNS) tumor classification since the advent of the WHO 2021 CNS tumor classification. However, in most of the low-income countries and middle-income countries, access to advanced molecular platforms remains limited due to cost, technical complexity, and turnaround time. Surrogate immunohistochemistry markers for mutation-specific or fusion-specific antibodies that reliably predict underlying genetic alterations offer a rapid, cost-effective alternative. The manuscript systematically discusses a spectrum of CNS tumor entities where morphology supplemented with immunohistochemistry can, in many cases, support an integrated molecular diagnosis, including "Astrocytoma, IDH-mutant" (IDH R132H, ATRX, and p53), "Oligodendroglioma, IDH-mutant, and 1p/19q codeleted" (HIP1R, H3K27me3 loss, and vimentin), "Diffuse midline glioma, H3K27-altered" (H3K27M, EZHIP), "Diffuse hemispheric glioma, H3G34-mutant" (H3G34R/V), "Infant-type hemispheric glioma" (Pan-TRK, ALK), "Epithelioid glioblastoma" and "Pleomorphic xanthoastrocytoma" (BRAF V600E)), "Astroblastoma, MN1-altered" (MN1), "Ependymoma" subtypes (p65, L1CAM, EZHIP), "Medulloblastoma" subgroups (β-catenin, LEF1, YAP1, GAB1), "Atypical teratoid/rhabdoid tumor" (SMARCB1, SMARCA4), "CNS neuroblastoma, FOXR2-activated" (FOXR2), "CNS tumor with BCOR ITD" (BCOR), and various sarcomas and sellar tumors (STAT6, NKX2.2, DUX4, β-catenin, BRAF V600E). For each entity, detailed morphologic features, immunoprofiles, sensitivity/specificity data, and diagnostic caveats have been described. The review emphasizes that when interpreted alongside histomorphology and conventional markers, surrogate immunohistochemistry can significantly reduce reliance on molecular testing, expedite diagnosis, and improve accessibility of precision diagnostics. Standardization, validation, and awareness of pitfalls remain essential to maximizing their clinical utility in neuropathology practice.