From depth to distribution: Multimodal PRAME analysis improves prognostication and surgical planning in acral melanoma

Summary: The purpose of this study was to develop and validate a combined 2D/3D approach integrating tumor depth assessment with quantitative PRAME expression for improved pre-operative acral melanoma evaluation. We employed complementary approaches using 3D pathological analysis with tissue clearing, immunofluorescent staining, and volumetric imaging to characterize PRAME spatial distribution, along with clinicopathological analysis on 88 acral melanoma specimens. Using QuantCenter® software, we developed a depth-PRAME combined (D-PRAMEC) scoring system. Our 3D visualization revealed that PRAME-positive cells predominantly localize to invasive borders. Quantitative 2D analysis demonstrated that PRAME expression positively correlates with aggressive histological features (necrosis, increased mitoses, ulceration). The D-PRAMEC scoring system effectively stratified patients into prognostic groups. In multivariate analysis, high D-PRAMEC levels independently predicted progression-free survival (aHR 5.78, 95% CI 1.97-16.98, p=0.001). Notably, patients with medium/high D-PRAMEC scores showed significantly higher progression risk than those with low scores. Our approach combines 3D PRAME distribution mapping with quantitative 2D analysis to better characterize tumor architecture and prognostic information compared to conventional assessment. This integrated methodology enhances pre-operative decision-making for acral melanoma surgery, particularly in planning margins and predicting aggressive disease behavior. Yuan-Chin Fu¹, Yi-Cheng Xiao², Cheng-Lin Wu¹ 1. Pathology Department, National Cheng Kung University Hospital, Tainan, Taiwan. 2. School of Medicine, National Cheng Kung University, Tainan, Taiwan. Bioinformatics, Computational Biology, and Imaging