Department of Pathology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu, Sichuan, China.
PeerJ. 2023 Aug 28;11:e15920. doi: 10.7717/peerj.15920. eCollection 2023.
Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification. We aimed to assess the utility of immunohistochemistry (IHC) staining for MMR protein expression and polymerase chain reaction (PCR)-based MSI assays in EC and the correlation between MMR/MSI status and various clinicopathological parameters.
We reviewed the clinical and pathological information of 333 patients with EC. MMR protein expression was assessed as retained or lost to determine MMR status by IHC staining, and MSI status was identified by PCR capillary electrophoresis (PCR-CE) testing with a National Cancer Institute (NCI) panel. The correlation of MMR/MSI status with clinicopathological features was determined by statistical analysis. Discrepant results were further analyzed using an alternative PCR-CE MSI (Promega panel) method, MLH1 promoter methylation assays, and next-generation sequencing (NGS).
Among the EC patients, the overall percentage of dMMR was 25.2%, and the overall percentage of MSI-H was 24%. Among the dMMR patients, 50 (59.5%) showed loss of MLH1 and PMS2 expression, 19 (22.6%) loss of MSH2 and MSH6 expression, and seven (8.3%) and eight (9.5%) loss of PMS2 and MSH6 expression, respectively. The dMMR subgroup was significantly younger than the pMMR subgroup, especially for <60-years-old patients ( = 0.038). In addition, we identified a strong correlation between MMR/MSI status and high-grade endometrioid or nonendometrioid components ( = 0.004 or = 0.003). IHC staining and PCR-CE assay results showed a high level of overall concordance (98.8%, Cohen's = 0.98). Four patients were found to have dMRR/MSS in both examinations. We reanalyzed them with additional methods. One case showed MLH1 promotor methylation, and the other three cases harbored MSH6 germline pathogenic variations. One of the cases with MSH6 deficiency was reanalyzed as MSI-H by alternative PCR-CE assay or NGS testing.
This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.
识别存在错配修复缺陷（dMMR）或微卫星不稳定高（MSI-H）的子宫内膜癌（EC）对于林奇综合征的筛查和治疗分层至关重要。我们旨在评估免疫组织化学（IHC）染色法检测错配修复蛋白表达和聚合酶链反应（PCR）检测微卫星不稳定性（MSI）在 EC 中的应用，并分析 MMR/MSI 状态与各种临床病理参数之间的相关性。
我们回顾了 333 例 EC 患者的临床和病理信息。通过 IHC 染色确定 MMR 蛋白表达是否保留或缺失，以确定 MMR 状态，通过国家癌症研究所（NCI）面板的 PCR 毛细管电泳（PCR-CE）检测确定 MSI 状态。通过统计分析确定 MMR/MSI 状态与临床病理特征的相关性。通过使用替代 PCR-CE MSI（Promega 面板）方法、MLH1 启动子甲基化检测和下一代测序（NGS）进一步分析不一致的结果。
在 EC 患者中，dMMR 的总体比例为 25.2%，MSI-H 的总体比例为 24%。在 dMMR 患者中，50 例（59.5%）表现为 MLH1 和 PMS2 表达缺失，19 例（22.6%）表现为 MSH2 和 MSH6 表达缺失，7 例（8.3%）和 8 例（9.5%）分别表现为 PMS2 和 MSH6 表达缺失。dMMR 亚组明显比 pMMR 亚组年轻，尤其是 60 岁以下的患者（=0.038）。此外，我们发现 MMR/MSI 状态与高级别子宫内膜样或非子宫内膜样成分之间存在很强的相关性（=0.004 或=0.003）。IHC 染色和 PCR-CE 检测结果显示总体一致性很高（98.8%，Cohen's =0.98）。有 4 例患者在两种检查中均表现为 dMRR/MSS。我们使用其他方法重新分析了他们。有 1 例表现为 MLH1 启动子甲基化，另外 3 例携带 MSH6 种系致病性变异。其中 1 例 MSH6 缺陷病例经替代 PCR-CE 检测或 NGS 检测重新分析为 MSI-H。
本研究表明，联合使用 MMR-IHC 和 PCR-CE MSI 分析可有效避免错配修复缺陷（dMMR）/微卫星不稳定高（MSI-H）的 EC 患者误诊。然而，单独使用 PCR-CE 评估 MMR/MSI 状态可能会导致漏诊，尤其是对于 MSH6 缺陷且表现为 MSS 的 EC 患者。
