Significance of MMR-IHC and MSI-PCR in different organ systems
Classic dMMR findings
Unusual dMMR findings
Isolated loss of PMS2 or MSH6
Discordance between MMR-IHC and MSI-PCR
Complex findings on IHC
Weak staining | TU: IC | Interpretation |
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MLH1/PMS2 | < / ~ | Normal |
MLH1/PMS2 | < / n | Both abnormal |
MLH1/PMS2 | ~ / < | PMS2 questionable |
MLH1/PMS2 | n / < | Both abnormal |
MSH2/MSH6 | < or n / ~ | MSH2 questionable; probably secondary (somatic) due to POLE mutation |
MSH2/MSH6 | < / n | Both abnormal |
MSH2/MSH6 | ~ / < | MSH6 abnormal |
MSH2/MSH6 | n / < | Both abnormal |
Subclonal loss | Abrupt loss of expression | Interpretation |
MLH1/PMS2 | Both | Clonal MLH1 methylation or germline mutation |
MSH6 with MLH1/PMS2 dMMR | MSH6 only | Secondary mutation in coding region of MSH6 (C8 repeat) |
MLH1/PMS2, MSH2/MSH6, PMS2 alone or MSH6 alone | Both or alone | May be genetic (germline genetics work-up) |
Multiple complete loss of expression | Each with pos. IC | Interpretation |
MLH1/PMS2 and MSH6 | 3 proteins | Secondary mutation in coding region of MSH6 (C8 repeat) |
MLH1/PMS2 and MSH2/MSH6 | 4 proteins | Secondary mutation in intronic MSH2 repeat (BAT25) |
Update on step-by-step assessment of MMR-IHC
Practical conclusion
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DNA mismatch repair deficiency (dMMR) determined by immunohistochemistry (MMR-IHC) is closely correlated (> 98%) with the microsatellite instability (MSI) detection using PCR (MSI-PCR) in cases of colorectal cancer (CRC). Discordances between the two methods occur in approx. 5–10% of other gastrointestinal tumors and in endometrial cancer, as well as in up to 40% of other tumors.
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For cancers other than CRC, MMR-IHC shows better performance than MSI-PCR as long as stringent quality criteria (choice of antibodies, staining protocol and evaluation) are observed. Optimal fixation is essential for all methods.
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Traditionally, dMMR was defined as the complete loss of expression of an MMR protein. Today, it is recommended to view the retention of staining in the entire tumor as mismatch repair proficient (pMMR) and to classify any deviation (complete or partial loss) as dMMR (abnormal).
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In practice, IHC findings should be grouped into normal (all MMR proteins positive) and abnormal with either classic dMMR (complete loss of expression of the two corresponding proteins in the heterodimer) or abnormal findings that deviate from this. Lynch syndrome is frequently associated with the latter and can be confirmed by germline genetic testing.
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Tumors with classic dMMR and/or high-grade microsatellite instability (MSI-H) are suitable for immune checkpoint inhibitor therapy. There is uncertainty in the case of reduced/heterogeneous MMR protein expression without MSI‑H. Careful review of all findings including matching of samples, and, if necessary, further molecular investigation (e.g., next-generation sequencing) are required.