This review offers a distinctive perspective by integrating and critically evaluating the latest advancements in non-invasive biomarkers for Prostate-Specific Antigen (PSA) gray-zone prostate cancer. By synthesizing data on Prostate Health Index (PHI), Prostate Cancer Antigen 3 (PCA3), Transmembrane Protease Serine 2-ETS-related Gene fusion (TMPRSS2-ERG fusion gene), proteomics, and microRNA (miRNAs), this work highlights their potential to enhance diagnostic precision while minimizing unnecessary biopsies. Furthermore, this review explores the clinical applicability of these biomarkers, bridging the gap between research innovations and real-world diagnostic strategies.The primary objective of this review is to analyze emerging biomarkers and clinical indicators that address the inherent diagnostic uncertainties within the PSA gray zone (4-10 ng/mL).Given the overlap between benign and malignant conditions in this range, traditional PSA-based screening lacks specificity, often leading to overdiagnosis and overtreatment.This review critically examines the diagnostic performance of the free PSA/total PSA (fPSA/tPSA) ratio, the Prostate Health Index (PHI), and molecular markers such as PCA3 and TMPRSS2-ERG fusion genes.Additionally, we discuss the integration of proteomic and miRNA-based approaches, emphasizing their potential role in refining risk stratification and advancing non-invasive prostate cancer diagnostics. A systematic review was conducted focusing on peer-reviewed research from databases such as PubMed, MEDLINE, and others.The studies included reported diagnostic accuracy, sensitivity, specificity, and clinical outcomes for biomarkers associated with PSA gray-zone prostate cancer.The inclusion criteria emphasized studies that evaluated human subjects and presented measurable diagnostic outcomes related to fPSA/tPSA ratio, PHI, PCA3, TMPRSS2-ERG, and additional protein-based biomarkers. The findings reveal that the fPSA/tPSA ratio enhances diagnostic sensitivity and specificity, making it a valuable tool within the PSA gray zone.PHI demonstrates superior diagnostic accuracy compared to traditional markers like tPSA.Molecular markers, such as PCA3 and TMPRSS2-ERG fusion genes, show considerable potential for distinguishing between benign and malignant conditions, effectively reducing the need for unnecessary biopsies.Additionally, proteomics and glycoprotein biomarkers offer non-invasive diagnostic possibilities, although further validation is necessary to confirm their efficacy. Incorporating multiple biomarkers, including the fPSA/tPSA ratio, PHI, PCA3, and TMPRSS2-ERG, presents a more accurate and patient-friendly approach to diagnosing PSA gray-zone prostate cancer.This multi-marker strategy enhances diagnostic precision, reduces biopsy rates, and supports the early detection of aggressive disease forms, representing a significant step forward in prostate cancer management and prognosis.
Ahamed et al. (Mon,) studied this question.