The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

Abstract

The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch repair-deficient (MMRd) tumors in endometrial cancer (EC). Identification of MMRd tumors, which occur in 13% to 30% of all ECs, has become critical for patients with colorectal and endometrial cancer for therapeutic management, clinical decision making, and prognosis. This review was conducted by two authors applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following terms: “immunohistochemistry and microsatellite instability endometrial cancer” or “immunohistochemistry and mismatch repair endometrial cancer” or “immunohistochemistry and mismatch repair deficient endometrial cancer”. Among 596 retrieved studies, 161 fulfilled the inclusion criteria. Articles were classified and presented according to their interest for the diagnosis, prognosis, and theragnostics for patients with MMRd EC. We identified 10, 18, and 96 articles using IHC expression of two, three, or four proteins of the MMR system (MLH1, MSH2, MHS6, and PMS2), respectively. MLH1 promoter methylation was analyzed in 57 articles. Thirty-four articles classified MMRd tumors with IHC markers according to their prognosis in terms of recurrence-free survival (RFS), overall survival (OS), stage, grade, and lymph node invasion. Theragnostics were studied in eight articles underlying the important concentration of PD-L1 in MMRd EC. Even though the role of IHC has been challenged, it represents the most common, robust, and cheapest method for diagnosing MMRd tumors in EC and is a valuable tool for exploring novel biotherapies and treatment modalities.

Correlation of PD-L1 immunohistochemical expression with microsatellite instability and p53 status in endometrial carcinoma

“…Previous studies found that combined PD-L1 positivity and MMR deficiency was associated with adverse findings, such as high tumour grade [10] ; therefore, there is a potential role for immunotherapy to benefit EC patients with MMR deficiency [6] , [7] , [9] , [12] . The association found between PD-L1 positivity and MMR deficiency in the present study was lower than reported previously [28] . This could be attributed to sampling and TMA matters.…”

Dostarlimab: From preclinical investigation to drug approval and future directions

“… 10 Most commonly, MSI-H endometrial cancer is associated with the methylation of MLH1 promoter. 11 , 12 MSI-H endometrial cancers are characterized by lower stage and intermediate prognosis. 13 , 14 In the Le et al study, endometrial cancer represented the second most common malignancy with MMR deficiency, accounting for 17% of the enrolled patients ( N = 15).…”

Applicability of the FDA-approved Immunohistochemical Panel for Identification of MMRd Phenotype in Uterine Endometrioid Carcinoma

“…G enomic and transcriptomic analyses of endometrial carcinoma (EC) have shown that 25% to 30% of tumors harbor a high frequency of somatic mutations that are attributable to deficiencies of DNA mismatch repair (dMMR), resulting in chromosomal changes referred to as microsatellite instability high (MSI-H). 1 This alteration of chromosomal biology and the resulting high mutation rate are thought to increase the expression of tumor-associated neoantigens, making MSI-H tumors logical targets for immunotherapy. In 2017, pembrolizumab as a single agent received accelerated approval by the US Food and Drug Administration (FDA) for treatment of refractory dMMR/MSI-H solid tumors, including EC.…”

“…[4][5][6] In 2019, the European Society for Medical Oncology (ESMO) consensus recommendations indicated immunohistochemistry (IHC) as the first test of choice for the 4 key MMR proteins and molecular analysis of the dMMR phenotype for mandatory confirmation if MMR immunohistochemical analysis (MMR-IHC) yielded a doubtful result. 1 Then, in 2022, the FDA approved a label expansion for the Ventana MMR RxDx Panel as the first IHC companion diagnostic test to help identify patients with dMMR solid tumors who may be eligible for immune checkpoint blockade monotherapy with pembrolizumab. The panel is also the first companion diagnostic test to help identify patients with EC whose tumors show proficient MMR (pMMR), and who may be eligible for combination therapy with pembrolizumab and the tyrosine kinase inhibitor lenvatinib.…”

“…As screening for dMMR by immunohistochemistry yields results highly concordant with the PCR-based assay, as well as being more cost-effective, accessible, and efficient, it has now become the preferred screening method 4–6 . In 2019, the European Society for Medical Oncology (ESMO) consensus recommendations indicated immunohistochemistry (IHC) as the first test of choice for the 4 key MMR proteins and molecular analysis of the dMMR phenotype for mandatory confirmation if MMR immunohistochemical analysis (MMR-IHC) yielded a doubtful result 1 . Then, in 2022, the FDA approved a label expansion for the Ventana MMR RxDx Panel as the first IHC companion diagnostic test to help identify patients with dMMR solid tumors who may be eligible for immune checkpoint blockade monotherapy with pembrolizumab.…”