Immunohistochemical Expression Profile of Mismatch Repair Proteins (MLH1, PMS2, MSH2, and MSH6) as a Surrogate of Microsatellite Instability and Clinicopathological Correlation in Endometrial Carcinoma
Gowtham Shanmugam, C. D. Anand, Nivethitha Sridharan, Muthu SudalaimuthuAbstract
Background:
Endometrial carcinoma (EC) is the most common gynecological malignancy in developed countries and the second most common globally. Mismatch repair (MMR) protein deficiency (dMMR), detected by immunohistochemistry (IHC), serves as a surrogate marker for microsatellite instability (MSI) and carries significant diagnostic, prognostic, and therapeutic implications, particularly for Lynch syndrome screening and eligibility for immune checkpoint inhibitor therapy.
Aim and Objectives:
To evaluate the immunohistochemical expression profiles of four MMR proteins, such as MLH1, PMS2, MSH2, and MSH6 in endometrioid EC, and to correlate MMR deficiency status with clinicopathological parameters including histological grade, depth of myometrial invasion, lymphovascular invasion (LVI), lower uterine segment (LUS) involvement, tumor-infiltrating lymphocytes, MELF pattern, FIGO stage, and lymph node status.
Materials and Methods:
A cross-sectional observational study was conducted at the Department of Pathology, SRM Medical College Hospital and Research Centre, total 50 hysterectomy specimens of endometrioid EC (January 2023–February 2026). IHC for MLH1, PMS2, MSH2, and MSH6 was performed on formalin-fixed paraffin-embedded tissue using validated antibodies. Loss of nuclear staining in tumor cells with intact internal controls was defined as deficient MMR (dMMR). Statistical analysis was performed using Pearson’s Chi-square test.
Results:
The mean patient age was 57.56 ± 9.42 years. All cases were FIGO Grade I (52%), II (40%), or III (8%). Loss of MLH1 was observed in 68%, PMS2 in 66%, MSH2 in 36%, and MSH6 in 46% of cases. Combined MLH1/PMS2 loss (dMMR pattern I) was seen in 64% and MSH2/MSH6 loss (dMMR pattern II) in 30% of cases. Overall, 76% of cases demonstrated at least one MMR protein loss. Highly significant concordant co-loss was confirmed for MLH1 and PMS2 (χ
2
= 37.434,
Conclusion:
This study highlights the high frequency of mismatch repair protein loss in endometrioid EC and notable loss of the MLH1/PMS2 pathway. Our results indicated significant interconnections between paired MMR proteins and implied possible connection between MMR deficiency and LVI. The immunohistochemical analysis of MMR proteins is an important diagnostic and screening methodology for the identification of mismatch repair deficiency and possible cases in association with the Lynch syndrome.