Peiró Gloria, Diebold Joachim, Lohse Peter, Ruebsamen Heike, Lohse Pia, Baretton Gustavo B, Löhrs Udo
Institute of Pathology and the Department of Clinical Chemistry, Grosshadern Hospital Ludwig-Maximilian University of Munich, Munich, Germany.
Hum Pathol. 2002 Mar;33(3):347-54. doi: 10.1053/hupa.2002.32220.
Microsatellite instability (MSI) due to replication errors occurs frequently in hereditary tumors. Association with functional inactivation of the mismatch repair (MMR) genes and lack of protein expression has been described. In endometrial carcinoma (EC), the prevalence and clinical significance of these phenomena are not well known. Therefore, DNA samples from 89 EC and 5 metachronous tumors were analyzed with polymerase chain reaction, using 5 microsatellite markers and a DNA sequencer for amplicon detection. The results were correlated with immunohistochemistry of hMLH1 and hMSH2. MSI at >or=2 loci (MSI-H) was detected in 10/89 EC (11%); 1 of 10 showed loss of both hMLH1 and hMSH2, and 5 of 10 showed loss of hMLH1 (P < 0.0001). MSI-H was observed frequently in tumors with mucinous differentiation (P = 0.048), >10% of solid-cribriform pattern (P = 0.037), International Federation of Obstetrics and Gynecology (FIGO) stage III to IV (4 of 13; P = 0.016), and necrosis >5% (P = 0.07). Loss of heterozygosity (LOH) in >or=1 loci was found in 17 of 156 (11%). Survival (Kaplan-Meier) was longer for patients with endometrioid tumors with predominant glandular pattern, <5% necrosis, low FIGO stage and grade, superficial myometrial infiltration, no lymph-vascular invasion (LVI), and loss of hMLH1 expression (all P <or= 0.04). Cox analysis showed independent value for stage, grade, histologic type and pattern, LVI, and hMLH1 expression (all P < 0.05). Age, MSI status, LOH, peritumoral inflammatory reaction, hMSH2, and development of metachronous tumors did not influence survival. In conclusion, MSI phenotype was observed in a small subset of mainly advanced-stage EC, frequently showing mucinous differentiation, areas of solid-cribriform pattern, and necrosis. It is often associated with loss of hMLH1 expression, which may be a prognostic marker, but only rarely with defects of hMSH2.
由于复制错误导致的微卫星不稳定性（MSI）在遗传性肿瘤中频繁发生。已有研究描述了其与错配修复（MMR）基因功能失活及蛋白表达缺失的关联。在子宫内膜癌（EC）中，这些现象的发生率及临床意义尚不清楚。因此，我们使用5个微卫星标记及DNA测序仪检测扩增子，通过聚合酶链反应对89例EC及5例异时性肿瘤的DNA样本进行分析。结果与hMLH1和hMSH2的免疫组化结果相关。在89例EC中有10例（11%）检测到≥2个位点的MSI（MSI-H）；10例中的1例显示hMLH1和hMSH2均缺失，10例中的5例显示hMLH1缺失（P<0.0001）。MSI-H在黏液性分化的肿瘤中常见（P = 0.048），在实性筛状模式占比>10%的肿瘤中常见（P = 0.037），在国际妇产科联盟（FIGO）III至IV期肿瘤中常见（13例中的4例；P = 0.016），在坏死>5%的肿瘤中常见（P = 0.07）。在156例中有17例（11%）发现≥1个位点的杂合性缺失（LOH）。对于具有主要为腺样模式、坏死<5%、FIGO分期及分级低、浅肌层浸润、无淋巴血管浸润（LVI）且hMLH1表达缺失（所有P≤0.04）的子宫内膜样肿瘤患者，其生存时间（Kaplan-Meier法）更长。Cox分析显示分期、分级、组织学类型及模式、LVI和hMLH1表达具有独立的预后价值（所有P<0.05）。年龄、MSI状态、LOH、肿瘤周围炎症反应、hMSH2及异时性肿瘤的发生不影响生存。总之，MSI表型在一小部分主要为晚期的EC中观察到，常表现为黏液性分化、实性筛状模式区域及坏死。它常与hMLH1表达缺失相关，hMLH1表达缺失可能是一个预后标志物，但与hMSH2缺陷很少相关。
