Spatial Transcriptomics Meets Histochemistry: Insights from Glioblastoma as a Model System.

High-resolution spatial transcriptomics has emerged as a powerful approach for linking genome-wide gene expression with preserved tissue architecture, enabling new insights into cellular heterogeneity and microenvironmental organization in complex tissues. In neuropathology, where morphological context is central to disease interpretation, these technologies are particularly appealing. Using glioblastoma multiforme (GBM) as a representative and highly heterogeneous model, this review critically evaluates the strengths and limitations of high-resolution spatial transcriptomic platforms in relation to classical histochemistry and cytochemistry. Illustrative analyses of human GBM tissue demonstrate that spatial transcriptomics robustly captures disease-relevant gene expression patterns and enables comprehensive mapping of key pathological features, including pseudopalisading necrosis, aberrant tumor vasculature, and therapy-resistant tumor niches. When integrated with histopathological observations, spatially resolved transcriptomic data can generate biologically meaningful hypotheses, offering insight into immune suppression, and proliferative signaling networks. These examples underscore the potential of spatial transcriptomics to bridge morphology and molecular biology, thereby expanding the conceptual framework of histopathological research. At the same time, spatial transcriptomic data should not be regarded as a replacement for direct microscopic evaluation. Limitations in morphological fidelity, lack of subcellular resolution, indirect inference of functional states, and reliance on computational interpretation necessitate careful integration with established histochemical and immunohistochemical methods. Without a solid foundation in tissue and cellular morphology, spatial transcriptomic findings may be misinterpreted or overstated. Collectively, this review emphasizes that spatial transcriptomics and histochemistry are complementary approaches, whose effective integration depends critically on rigorous histochemical knowledge to ensure accurate pathological interpretation and translational relevance.