Isolated MSH2 Loss With Divergent Microsatellite Instability Status in Colorectal and Prostate Adenocarcinoma: A Diagnostic Pitfall

Background The fidelity of the DNA mismatch repair (MMR) system is routinely evaluated using MMR immunohistochemistry (IHC). The MMR IHC is interpreted based on obligate heterodimeric relationships (MLH1-PMS2; MSH2-MSH6). MSH2 loss typically results in concurrent MSH6 loss. Atypical non-dimer patterns, such as isolated loss of MSH2 with retained or patchy MSH6, complicate reflex testing and genotype inference. Patient presentation Patient 1 was a 90-year-old woman with an ascending colon mass. Biopsy showed invasive moderately differentiated colorectal adenocarcinoma. MMR IHC demonstrated isolated loss of MSH2 with heterogeneous/patchy MSH6 retention. Polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing was reported as microsatellite stable (MSS). Targeted testing showed no KRAS / NRAS or BRAF V600E mutations. Patient 2 was a 70-year-old man with recurrent high-grade prostatic carcinoma sampled by transurethral resection of the prostate (TURP) from the pelvic bed. MMR IHC demonstrated intact MLH1/PMS2/MSH6 with isolated loss of nuclear MSH2, accompanied by very faint cytoplasmic staining. These IHC findings were reproduced on an additional block. MSI testing was reported as MSI-High (MSI-H). Conclusion A focused literature review identified this non-dimeric pattern of isolated MSH2 loss across multiple tumor types, most commonly colorectal, prostate, and endometrial carcinomas. Our paired findings illustrate that this non-dimeric pattern may coexist with either MSS or MSI-H status, underscoring that MMR IHC patterns should be confirmed for repeatability and interpreted in the context of clinicopathologic and molecular correlation.