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M 60ish. Caecal tumour ! Poorly differentiated , typical dMMR morphology ! MMR IHC - all four stains negative with adequate internal control ! How would you approach this? What would you do next in terms of work up or advice to clinicians ? #gipath #frcpath #PathTwitter 
Thank you all for engaging. This is really rare but once in a while, we do come across cases showing more than two markers' loss. Previously I had recommended genetic referral in such an instance thinking loss of MSH2/MSH6 is almost always germline i.e syndromic. 1/2
However, recently heard a talk on MSI & became aware that in most such cases, the MLH1 hypermethylation is a primary event and loss of MSH6 is secondary sporadic mutation. These patients in fact do not harbor germline mutation. Subsequently, I also found the following reference.
