Abstract
BACKGROUND: Prostate Cancer (PCa) is a heterogeneous disease, where hypoxia and cribriform growth have been established as adverse prognostic features. Hypoxia refers to a condition of limited oxygen concentration within the tumor microenvironment, associated with enhanced tumor aggressiveness, resistance to therapy, and poor clinical outcome. Likewise, cribriform growth has also been related to poor prognosis, though the biologic basis remains unclear. Recent pathological studies suggest that there is an association between cribriform growth and tumor hypoxia, but evidence from PCa patient studies are scarce. To fill this knowledge gap, this study aims to investigate the association between hypoxia measured by MR imaging and cribriform growth identified in whole-mount histological specimens. METHODS: A retrospective cohort of 291 patients with biopsy-confirmed PCa who underwent radical prostatectomy and pre-operative MRI was analyzed. Tumors were graded according to the 2019 ISUP classification, and cribriform growth presence and length were assessed on whole-mount histology. The oxygen consumption and supply based model using apparent diffusion coefficient and fractional blood volume was applied to estimate hypoxia level (HL) and hypoxia fraction (HF(DWI)). Differences in HL and HF(DWI) across Gleason patterns and between cribriform growth-positive and -negative tumors were assessed. Furthermore, a linear regression model was used to evaluate the association between cribriform growth and hypoxia after adjusting for confounders. RESULTS: Cribriform growth-positive tumors exhibited significantly higher HF(DWI) values compared to cribriform growth-negative tumors (p < 0.001). Within individual cancer Grade Groups (GG), cribriform growth length was significantly associated with increased HF(DWI) in pGG 3 tumors. HL(median) values were highest in Gleason Pattern 3 (GP3) regions and lowest in cribriform growth (GP4Crib+) regions, with significant differences observed between GP3 vs. non-cribriform growth GP4 regions (p < 0.001) and GP3 vs. GP4Crib+ (p < 0.001), consistent with more hypoxia in GP4Crib+. Multivariable regression confirmed cribriform growth presence as an independent predictor of increased hypoxia fraction, even after adjusting for tumor volume and GG. CONCLUSIONS: This study shows an association between cribriform growth and tumor hypoxia using an MRI-based biomarker. These findings provide further biological insights into the aggressive nature of cribriform growth architecture and highlight the potential clinical utility of non-invasive hypoxia quantification for risk stratification in prostate cancer management. CLINICAL TRIAL NUMBER: Not applicable.