BackgroundThe significance of perineural invasion (PNI) in prostate cancer (PC) is unclear. A recent report of patients with pT2N0R0 PC found that PNI at prostatectomy was independently associated with higher Gleason score and more diffuse prostatic disease. We aimed to test our hypothesis that PNI on prostate biopsy in pT2N0R0 patients is associated with increased Gleason score upgrading at prostatectomy.MethodsWe identified 2892 patients status post prostatectomy with pT2N0R0 PC from three institutions, diagnosed between 1 January 2008 and 31 December 2014. Multivariable logistic regression (MVA) was used to evaluate the association between prostate biopsy PNI status and surgical Gleason upgrading, while controlling for potential confounders.ResultsOf the 2892 patients identified, 14% had PNI on biopsy, of whom 21% had surgical Gleason upgrading, while 28% without PNI on biopsy had such upgrading (P < .01). On MVA, the odds ratio (OR) of surgical Gleason upgrading for patients with biopsy PNI relative to patients without biopsy PNI was 0.69 (P < .01). The variables associated with surgical Gleason upgrading were age ≤60 years (OR 1.22, P = .02) and preoperative PSA >4 ng/mL (OR 1.26, P = .02).ConclusionsIn post‐prostatectomy patients with favorable‐risk PC, PNI on prostate biopsy was not associated with surgical Gleason score upgrading. This may be due to the association of PNI with more diffuse disease, leading to increased biopsy tumor yield and grading accuracy. These findings suggest that in this setting, biopsy PNI alone should not be a concern for more aggressive disease requiring pathologic confirmation or intervention. This may help guide treatment decision‐making for men debating active surveillance, radiation, and surgery.