Table 1 Atypical mismatch repair protein immunohistochemistry staining patterns.
Tumor staining | Internal control | Interpretation | Technical/biological explanation |
|---|---|---|---|
Equivocal throughout | Weak or none | Staining not working, repeat test on same or different block | Typically due to poor fixation |
Focally weak or lost | Also weak or none in these foci | Regard these foci as non-interpretable, rely on the remaining interpretable regions for results (Fig. 4A, B) | Typically due to regional poor fixation, tissue degeneration, or poor exposure to antibody/reagents during staining |
Weaker than internal control | Present and optimal | Correlate with staining of its partner protein as follows: | |
MLH1 weak/PMS2 normal (Fig. 1C, D): - Report both as normal | |||
MLH1 weak/PMS2 abnormal (Fig. 1A, B): - Report both as abnormal | |||
MLH1 normal/PMS2 weak (unlikely scenario): - Report PMS2 as equivocal | |||
MLH1 abnormal/PMS2 weak (unlikely scenario): - Report both as abnormal | |||
MSH2 weak (or lost)/MSH6 normal (unlikely scenario): - Report MSH2 as equivocal | Have been observed in POLE-mutated cases, mechanism unclear | ||
MSH2 weak/MSH6 abnormal (Fig. 2): - Report both as abnormal | |||
MSH2 normal/MSH6 weak: - Report MSH6 as abnormal | |||
MSH2 abnormal/MSH6 weak (Fig. 4D, E): - Report both as abnormal | |||
Distinct clonal loss | Present and optimal | Report as abnormal: | |
Clonal loss of MLH1 and PMS2 (Fig. 3D–F) | Typically associated with clonal MLH1 methylation (maybe mutation as well, see below) | ||
Clonal loss of MSH6 in MLH1/PMS2-deficient tumors | Typically associated with secondary mutation of coding microsatellites in MSH6 in the tumor | ||
Clonal loss of MLH1/PMS2, MSH2/MSH6 (Fig. 3A–C), PMS2 alone, or MSH6 alone | Could potentially be associated with germline mutation, suggest genetic workup | ||
Cytoplasmic staining | - Mostly aberrant, regard as non-interpretable; rely on nuclear staining status for result interpretation - When occurring with MSH2, and accompanied by loss of nuclear staining, it could reflect EPCAM/MSH2 abnormality | In some EPCAM-Lynch syndrome cases, cytoplasmic localization of EPCAM-MSH2 fusion proteins can result in cytoplasmic MSH2 staining21,22 |
