MRI-invisible prostate cancer and the tumor microenvironment: an intra- patient paired transcriptomic and immunohistochemical study

BACKGROUND Multiparametric magnetic resonance imaging (mpMRI) has transformed prostate cancer (PCa) diagnosis, yet some clinically significant tumors remain undetectable. As mpMRI is integrated into guideline-based pathways, understanding the biological basis of MRI invisibility is clinically important. This study investigated molecular and microenvironmental determinants of such MRI invisibility through intra-patient comparisons of MRI-visible (MRI+) and MRI-invisible (MRI–) lesions. METHODS Among 980 men who underwent radical prostatectomy (2013–2023), 25 harbored both MRI + and MRI– intraprostatic foci. Laser microdissection was used to isolate paired MRI + and MRI– regions. RNA was extracted from nine patients; three with high-quality RNA underwent paired transcriptomic and immunohistochemical analyses. Differential expression and immunohistochemistry-based validation were performed, and interleukin-5 receptor alpha (IL5RA) was prioritized as a candidate marker. RESULTS Transcriptomic screening identified immune and cytokine-receptor pathways enriched in MRI– lesions, with IL5RA consistently upregulated in MRI– versus MRI+ regions. Immunohistochemistry confirmed predominance of IL5Rα-positive tumor cells in MRI– areas, and QuPath-based quantification showed higher H-scores in MRI– regions (mean paired difference: 76.3 ± 44.8). Additional MRI-negative cT1c and pathologic seminal vesicle invasion (pT3b) cases demonstrated concordant IL5RA expression, supporting this pattern beyond the discovery cohort. IL5RA encodes the α-subunit of the IL5R; its overexpression suggests a benign-like microenvironment that may diminish mpMRI conspicuity. CONCLUSIONS These findings nominate IL5RA signaling as a molecular correlate of MRI invisibility and a potential biomarker bridging tumor immunobiology and radiologic phenotype in PCa, with implications for biopsy targeting, focal-therapy selection, and preoperative risk stratification in men with negative or equivocal mpMRI findings.