Stromal FAP Expression is Associated with MRI Visibility and Patient Survival in Prostate Cancer

Some clinically significant prostate cancers are missed by MRI. We asked whether the tumor stroma in surgically treated localized prostate cancer lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease. We profiled the stromal and immune cell composition of MRI-classified tumor lesions by applying multiplexed fluorescence IHC (mfIHC) and automated image analysis in a clinical cohort of 343 patients (cohort I). We compared stromal variables between MRI-visible lesions, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and log-rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (cohort II). MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163⁺ cells (macrophages) and fibroblast activation protein (FAP)⁺ cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP⁺ cells was associated with PTEN status and increased immune infiltration (CD8⁺, CD163⁺), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC. The molecular composition of the tumor stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment.

These findings may have a significant impact on clinical decision making as more radical treatments may be recommended for men with a combination of MRI-visible primary tumors and FAP⁺ tumor stroma.