PSMA PET SUVmax Adds Information Beyond Conventional Risk Indices in Localized Prostate Cancer: A Prospective Lesion-Level Radiopathologic Study

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is increasingly used to characterize newly diagnosed prostate cancer on the assumption that uptake highlights aggressive disease. However, maximum standardized uptake value (SUVmax) varies widely across localized tumors. Recent genomic assessments have suggested SUVmax reflects tumor biology even when accounting for other tumor indices. Here, we examined highly annotated pathologic, imaging and clinical correlates of intraprostatic SUVmax at the level of individual tumor foci in a prospective multimodal cohort. Methods: Exploratory lesion-level analysis of the radical prostatectomy arm of a single-center prospective diagnostic-accuracy trial (NCT04461509). Patients underwent simultaneous 18F-DCFPyL PSMA PET, multiparametric magnetic resonance imaging (MRI) and high-resolution MRI before prostatectomy, with central blinded pathology and imaging review. Grade Group (GG) [≥]2 foci measuring [≥]10 mm were eligible. The primary outcome was focus-level SUVmax. Correlates spanning histology, tumor microenvironment, MRI and clinical indices were examined by Spearman correlation and rank-based group comparison, followed by separate linear regressions of log(1+SUVmax) each adjusted for GG and tumor size. A digital-pathology sensitivity analysis quantified immune, stromal and tumor pixel-area fractions on hematoxylin and eosin (H&E) sections from a subset of foci using a trained QuPath classifier. Results: Twenty-seven patients contributed 34 tumor foci, of which 21 (61.8%) were GG2. Median SUVmax was 5.7 (interquartile range [IQR] 3.9 - 12.1; range 0.0 - 57.9). SUVmax rose across the cribriform/intraductal carcinoma (Crib/IDC) gradient (median 3.9, 4.8 and 10.2 for absent, focal and extensive; p = 0.010), correlated with % Gleason pattern 4 ({rho} = +0.47, p = 0.005) and correlated inversely with stromal content ({rho} = - 0.40, p = 0.020). Grade Group (p = 0.115), Prostate Imaging Reporting and Data System (PI-RADS) 4 versus 5 (p = 0.705), standard apparent diffusion coefficient (ADC) ({rho} = - 0.27, p = 0.130), baseline prostate-specific antigen (PSA) ({rho} = +0.04, p = 0.816) and PSA density ({rho} = - 0.02, p = 0.918) were not associated with SUVmax. In separate models of log(1+SUVmax) adjusted for Grade Group and tumor size, % Gleason pattern 4 remained associated with uptake (standardized {beta} = +0.76, 95% CI +0.11 to +1.41), Crib/IDC ({beta} = +0.36, - 0.03 to +0.74), and stromal content ({beta} = - 0.30, - 0.62 to +0.02). On 18 slides re-quantified by pixel classifier, no pixel-based compartment fraction correlated with SUVmax (immune {rho} = - 0.06, stroma {rho} = +0.02, tumor {rho} = - 0.04; all p > 0.5). Conclusions: In this prospective lesion-level cohort, intraprostatic PSMA SUVmax was associated with increased Gleason pattern 4 and cribriform/intraductal burden but not with other common risk indices. SUVmax therefore appears to carry information additive to conventional risk factors. Further investigations examining the tumor biology that reflects SUVmax are warranted.