Neuroendocrine prostate cancer (NEPC) constitutes less than 1% of all prostate malignancies and shows a notably worse prognosis than conventional androgen receptor–positive prostate adenocarcinoma (ARPC). We encountered an exceptionally rare case in which de novo NEPC and ARPC coexisted within the same prostate specimen. This case provides an ideal model for investigating spatial gene expression differences between the two histologies.

Formalin-fixed, paraffin-embedded (FFPE) tumor tissue obtained from a 78-year-old male treated at Ehime University Hospital was analyzed using Visium CytAssist Spatial Gene Expression technology (10x Genomics). Spatial transcriptomic profiling was performed to identify differential gene expression signatures between ARPC and NEPC components.

NEPC regions showed elevated expression of neuroendocrine markers (PEG10, DLL3, NCAM1, SYP, and CHGA), while ARPC regions demonstrated upregulation of androgen receptor–related genes (KLK3, ACPP, TMPRSS2, and NKX3.1). NEPC also exhibited increased expression of Chek1, BRCA1/2, TOP2A, and FANCA, suggesting sensitivity to PARP and TOP2 inhibitors. Suppression of Rbfox3 and SFRTM2 was associated with potential epithelial–mesenchymal transition (EMT) and Wnt pathway involvement. Fibrotic and immunosuppressive markers (HGF, HMOX1, ELN, and GREM1) were enriched, indicating an “immune cold” tumor microenvironment.

Our findings highlight distinct molecular landscapes between de novo NEPC and ARPC within the same patient, providing new insights into potential therapeutic targets for NEPC. The accumulation of similar cases may help establish new therapeutic strategies for NEPC, a disease that currently lacks a standard treatment.