Scattered Nuclear Staining: A Novel Immunohistochemical Expression Pattern of Mismatch Repair Proteins and Its Significance in Endometrial Carcinoma

Background Immunohistochemical (IHC) analysis of mismatch repair (MMR) proteins is a widely accepted method for the routine screening of microsatellite instability (MSI) in endometrial carcinoma (EC). However, IHC may occasionally yield indeterminate results, exhibit suboptimal reproducibility, and carry a potential for misdiagnosis. This study aimed to propose a novel MMR IHC expression pattern and explore its clinical significance in EC. Methods Four hundred and seventy-five ECs were characterized using IHC and MSI testing. MMR/CK-pan dual staining confirmed the tumor cell identity of cells exhibiting scattered nuclear staining (SNS). Cases were stratified into four groups based on distinct MMR IHC expression patterns and compared for clinicopathological differences. Results Four hundred and seventy-five ECs were classified; 75% as mismatch repair-proficient (pMMR) group (intact expression of all 4 MMR proteins, ≥ 5% staining), 13% mismatch repair-deficient (dMMR) group (complete loss of expression of one or more MMR proteins), 2% subclonal group, and 10% as SNS group (< 5% staining). The dMMR group were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and significant lymphocyte infiltration around tumor. The SNS group demonstrated aggressive biological behavior similar to, yet distinct from the dMMR group, exhibiting a higher incidence of cervical stromal invasion and lymph node metastasis. MSI testing confirmed that 62.9% of SNS cohort exhibited microsatellite instability-high (MSI-H) status. Different combinations of MMR IHC patterns may provide indicative clues for MSI status. Conclusions SNS represents an objectively identifiable phenomenon within MMR IHC expression patterns and should be recognized as a distinct MMR IHC expression category. The establishment of this pattern not only addresses unmet needs in clinical practice but also complements the existing College of American Pathologists (CAP) guidelines.