Clinicopathologic Spectrum and Intraprostatic Heterogeneity of Primary Mismatch Repair-Deficient Prostate Cancer

Mismatch repair deficiency (MMRd) is identified in a small subset of prostate cancers and has implications for therapy selection and germline testing. The clinicopathologic spectrum of primary MMRd prostate cancer remains incompletely characterized. We evaluated 32 primary treatment-naive MMRd prostatic adenocarcinomas identified at a single institution. Grade group distribution included GG5 (n=12, 38%), GG4 (n=4, 13%), GG3 (n=7, 22%), and GG2 (n=9, 28%). Intraductal and/or invasive cribriform carcinoma was identified in 78% of cases overall and in 78% of GG2 tumors. MMR protein loss predominantly involved MSH2/MSH6 (78%), with isolated MSH6 loss in 16% and MLH1/PMS2 loss in 6%. Concordant pathogenic MMR gene alterations were identified on targeted NGS in all cases, while concurrent Tier 1/2 HRR gene alterations were present in 11 cases (35%), including ATM, BRCA1, and BRCA2. Germline testing performed in 15 cases identified Lynch syndrome in 5 (33%). MMR immunohistochemistry performed on multiple tissue blocks in 14 cases revealed discordant MMR status between tumor foci in 8 cases (57%), with MMR deficiency consistently restricted to the highest-grade focus and retained expression in spatially separate lower-grade foci. One additional case demonstrated apparent intratumoral heterogeneity within a single biopsy core, with MMR deficiency restricted to a higher-grade component and retained expression in the adjacent lower-grade tumor. These findings demonstrate a broader clinicopathologic spectrum of primary MMRd prostate cancer than previously recognized. Frequent discordance of MMR status between tumor foci highlights the importance of evaluating the highest-grade tumor focus when assessing multifocal primary prostate cancer.