Mismatch repair loss in prostate cancer was confined to the highest-grade focus in more than half of multiblock cases

Design

Single-institution retrospective case series

Population

32 primary treatment-naive mismatch repair-deficient prostate adenocarcinomas

Primary outcome

Clinicopathological features and intertumoral MMR heterogeneity

Effect

Discordant MMR status between foci in 8/14 multiblock cases (57%); Lynch syndrome in 5/15 tested

A single-institution series in The American Journal of Surgical Pathology (15 September 2026) described 32 primary, treatment-naive mismatch repair-deficient prostate adenocarcinomas. Grade ranged widely: 38% were grade group 5, but 28% were grade group 2. Cribriform or intraductal carcinoma was present in 78%, including 78% of the grade group 2 tumours. Loss mostly involved MSH2 and MSH6. Every case had a matching pathogenic MMR alteration on sequencing, and 35% also carried homologous recombination repair alterations, including ATM, BRCA1 and BRCA2. Of 15 patients who had germline testing, 5 had Lynch syndrome.

The key finding was heterogeneity. In 14 cases stained on more than one block, MMR status differed between tumour foci in 8. Deficiency was always in the highest-grade focus, with intact staining in separate lower-grade foci, and one biopsy core showed the same split within it.

This matters because MMR status now drives two decisions: eligibility for immune checkpoint treatment and referral for germline testing. Staining a convenient lower-grade block can miss deficiency that is there. The series is small and from one centre, but the direction of the error is consistent.

• When testing MMR in multifocal prostate cancer, stain the highest-grade focus.
• Consider staining more than one focus if the first result is intact and higher-grade tumour exists elsewhere.
• Look for cribriform or intraductal growth; it was common in deficient tumours, even at grade group 2.
• Recommend germline genetic counselling when MMR deficiency is found; a third of those tested had Lynch syndrome.
• Report which block was stained and its grade.

Why it matters

A lower-grade block can return a falsely intact result, costing a patient immunotherapy eligibility and a Lynch diagnosis.

Don't overread it

This is a small single-centre series; the frequency of discordance in unselected prostate cancers is unknown.

The statistics, in plain English

Eight of 14 is 57%, but the 14 were cases where multiple blocks happened to be stained, not a random sample. The true rate of discordance could be lower, though the finding that deficiency sat in the highest-grade focus every time is consistent.

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