Mismatch repair status in prostate cancer can differ by focus; test the highest-grade tumour

Design

Single-institution case series with targeted sequencing

Population

32 primary treatment-naive mismatch repair-deficient prostatic adenocarcinomas

Primary outcome

Clinicopathologic spectrum and concordance of mismatch repair status between foci

Effect

Discordant status in 8 of 14 cases (57%) tested on several blocks; Lynch syndrome in 5 of 15 tested (33%)

A single-institution series described 32 treatment-naive primary prostatic adenocarcinomas with mismatch repair deficiency. Grade group 5 made up 38%, grade group 4 13%, grade group 3 22% and grade group 2 28%. Intraductal or invasive cribriform carcinoma was present in 78%. Loss of MSH2/MSH6 predominated (78%), and targeted sequencing confirmed a pathogenic mismatch repair gene change in every case. Homologous recombination repair gene alterations co-occurred in 35%.

Germline testing in 15 patients identified Lynch syndrome in 5 (33%). In the 14 cases where immunohistochemistry was run on several blocks, 8 (57%) showed discordant status between foci: deficiency was confined to the highest-grade focus and lower-grade foci retained expression.

A result from a lower-grade block could therefore falsely read as proficient. The series is small, from one centre, and selected for deficient tumours, so it cannot give the true frequency of discordance. It does support choosing the highest-grade focus when testing a multifocal tumour.

• Select the block with the highest-grade tumour for mismatch repair immunohistochemistry in multifocal prostate cancer.
• Consider testing additional blocks when a lower-grade focus is stained and the clinical question matters.
• Mention in the report which block and grade was tested.
• Suggest germline counselling when deficiency is found; Lynch syndrome was found in about a third of those tested here.
• Note co-occurring cribriform or intraductal morphology, which was frequent in this series.

Why it matters

A single negative block may not mean the tumour is proficient, and that decision affects therapy options and family testing.

Don't overread it

This is a single-centre series of already-deficient tumours, so it does not give the prevalence of deficiency or of discordance.

The statistics, in plain English

Fourteen cases is too few to give a reliable discordance rate: 8 of 14 could plausibly correspond to a true rate anywhere from about a third to four-fifths. Because the cases were chosen for being deficient, they cannot tell you how often a negative result in a lower-grade block hides deficiency elsewhere.

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