Gatius Sonia, Vaquero Marta, Scheiber Oliver, Velasco Ana, Cuevas Dolors, Kashofer Karl, Santacana Maria, Eritja Núria, Lax Sigurd, Matias-Guiu Xavier
Hospital Universitari Arnau de Vilanova. IRBLleida, Universitat de Lleida, Av Rovira Roure 80, CIBERONC, Lleida, 25198, Spain.
Department of Pathology, General Hospital Graz II, Styrian Hospital Corporation, Graz, Austria.
Virchows Arch. 2025 Jun 5. doi: 10.1007/s00428-025-04132-3.
Mismatch repair (MMR) status in endometrial carcinoma (EC) is crucial for diagnosis, prognosis, treatment, and Lynch syndrome pre-screening. MLH1 loss is the most frequent cause of MMR deficiency and usually by promoter hypermethylation. We tried to confirm the role of EPM2 AIP1 immunohistochemistry as a surrogate of MLH1 promoter methylation in EC. Case series from two different institutions were analyzed by comparable methods using immunohistochemistry for MMR proteins and EPM2 AIP1, and pyrosequencing for MLH1 methylation. In the first series of 70 cases, concordance was 100%, after reassessing three cases with methylation scores close to cut-off, by tumor cell enrichment. In the second series of 29 MLH1-deficient ECs, concordance was 96.5%, while in the control group of 30 MMR-proficient EC, one MLH1-positive case was EPM2 AIP1-negative. EPM2 AIP1 immunoreactivity was qualitatively superior in curettages and biopsies compared to hysterectomy. We conclude that EPM2 AIP1 immunohistochemistry is a good surrogate for MLH1 promoter methylation analysis, cost-effective with short turnaround time, but needs attention regarding preanalytical handling, normal tissue contamination, or low tumor percentage.
子宫内膜癌（EC）中的错配修复（MMR）状态对于诊断、预后、治疗以及林奇综合征的预筛查至关重要。MLH1缺失是MMR缺陷最常见的原因，通常是由于启动子高甲基化。我们试图证实EPM2 AIP1免疫组化作为EC中MLH1启动子甲基化替代指标的作用。采用免疫组化检测MMR蛋白和EPM2 AIP1以及焦磷酸测序检测MLH1甲基化的可比方法，对来自两个不同机构的病例系列进行分析。在第一组70例病例中，通过肿瘤细胞富集重新评估了3例甲基化评分接近临界值的病例后，一致性为100%。在第二组29例MLH1缺陷的EC中，一致性为96.5%，而在30例MMR功能正常的EC对照组中，有1例MLH1阳性病例EPM2 AIP1阴性。与子宫切除术相比，刮除术和活检中EPM2 AIP1免疫反应性在质量上更优。我们得出结论，EPM2 AIP1免疫组化是MLH1启动子甲基化分析的良好替代指标，具有成本效益且周转时间短，但在分析前处理、正常组织污染或肿瘤比例较低方面需要注意。
