Background: Prostate cancer is a common malignancy among men worldwide, with various histopathologic features that influence its progression and prognosis. One such feature is perineural invasion (PNI), which has been associated with aggressive disease. In this retrospective study, we analyzed genomic alterations associated with PNI in patients who underwent radical prostatectomy. Methods: A total of 421 prostate cancer patients who underwent radical prostatectomy without neoadjuvant therapy were identified from The Cancer Genome Atlas. PNI was present in 378 patients (89.8%) and absent in 43 (10.2%). Differentially expressed genes were identified, and mRNA expression levels of key genes were analyzed. The prognostic significance of these genes was evaluated using log-rank tests and Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals. Results: Levels of COL9A3, ASPN, ESR1, MUC1, PIP, SFRP4, KRT19, CLDN1, and COMP were significantly higher in the tumor tissues of patients in the PNI group compared to those in the non-PNI group (q < 0.05), and RYR2, MME, and AZGP1 expression levels were significantly higher in the non-PNI group (q < 0.05). A high mRNA expression level of AZGP1 was associated with longer disease-free survival, whereas high mRNA expressions of ASPN, COMP, RYR2, and SFRP4 were associated with shorter disease-free survival. Conclusions: Prostate cancer patients with genomic alterations associated with PNI may face a higher risk of disease progression after prostatectomy, highlighting the need for further prospective studies to validate these findings.

Background/Objectives: Cribriform architecture is an adverse histopathologic feature in prostate cancer and has been associated with poor oncologic outcomes. Emerging evidence suggests that cribriform-positive tumors may behave as a biologically non-localized disease, raising the possibility of early occult dissemination. Lymphovascular invasion (LVI) is a key pathological marker of metastatic potential, but its relationship with cribriform architecture has not been evaluated. We examined the association between cribriform morphology and LVI to provide biological context for the aggressive clinical course of cribriform-positive prostate cancer. Methods: We performed a retrospective analysis of patients with prostate adenocarcinoma who underwent radical prostatectomy and had available clinicopathologic data. Cribriform architecture was determined by a centralized pathology review, and LVI status was obtained from original pathology reports. Unadjusted associations were evaluated using contingency tables. Multivariable logistic regression was used to assess whether cribriform architecture was independently associated with LVI after adjustments for Gleason score, tumor stage, and nodal status. Results: Among 338 patients, 28 (8.3%) had LVI and 123 (36.4%) had cribriform architecture. LVI was more common in cribriform-positive than cribriform-negative tumors (17.9% vs. 2.8%; p < 0.001), corresponding to a crude odds ratio (OR) of 7.6 (95% CI, 3.0–19.3). Cribriform architecture remained independently associated with LVI after adjustment (adjusted OR, 5.20; 95% CI, 2.12–1.40; p < 0.001). Conclusions: Cribriform architecture is strongly and independently associated with LVI, supporting a biological link between cribriform morphology and early metastatic dissemination. These findings support the design of prospective, biomarker-driven studies to evaluate treatment intensification strategies in this high-risk subgroup.