Molecular Profile of Grade 3 Endometrioid Endometrial Carcinoma: Is it a Type I or Type II Endometrial Carcinoma?
Molecular Profile of Grade 3 Endometrioid Endometrial Carcinoma: Is it a Type I or Type II Endometrial Carcinoma?
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DOI：
10.1097/pas.0b013e318247b7bb
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发表时间：
2012-05-01
影响因子：
5.6
通讯作者：
Oliva, Esther
中科院分区：
文献类型：
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作者：
Alvarez, Teresa;Miller, Ezra;Oliva, Esther
两种类型的子宫内膜癌（EC）已划定的基础上，临床病理研究。低级别类神经胶质细胞癌（EEC）是I型EC的原型，其特征在于微卫星不稳定性和PTEN、K-ras和/或β-连环蛋白基因突变，而II型EC通常以浆液性和透明细胞癌（SC/CCC）为代表，前者经常显示p53突变和c-erb-2过表达;然而，3级EEC的分子特征尚未得到很好的表征。本研究的目的是确定3级EEC的免疫组化和分子特征。我们研究了25例3级EEC患者，年龄从35岁到87岁（平均61岁）。在初次诊断时，16例患者患有I期肿瘤，而3例、5例和1例分别患有II期、III期和IV期肿瘤。仅1例IV期患者因肿瘤直接穿过子宫壁而发生腹膜病变。从石蜡包埋的组织块构建两个组织微阵列，并对MLH-1、MSH-2、p16、细胞周期蛋白D1、C-erb-B2、WT-1和p53进行染色。MLH-1和MSH-2的丢失分别见于25例肿瘤中的3例和24例肿瘤中的1例;无一例显示两者均丢失。弥漫性p16核表达被发现在23例中的7例;弥漫性和强的核免疫染色p53，细胞周期蛋白D1，和Her-2被认为是在9 24肿瘤，9 25，和3 25癌，分别。WT-1在所有25个肿瘤中均为阴性。3例Her-2过表达的3级EECs中有1例荧光原位杂交显示基因扩增。未发现细胞周期蛋白D1基因扩增，所有患者均获得随访信息。16例为I期肿瘤。其中11例生存良好（AW），3例死于疾病（DOD），2例死于无关原因（DUC），平均随访时间为56个月（范围：24 - 96个月）; 2/3例II期肿瘤患者为DOD，1例为AW，平均随访时间为81个月（范围，6至66个月）; 5例III期肿瘤患者中，2例DOD，1例AW，1例肺转移存活，1例DUC [平均随访时间为29个月（范围，12至74个月）];唯一的患者在12个月后出现IV期肿瘤DOD。有趣的是，3级EEC显示MLH-1/MSH-2缺失的患者具有I期肿瘤，并且全部为AW（60至84个月）。77%（7/9）的肿瘤细胞周期蛋白D1过度表达的患者为I期，无一例死于疾病，而85%（6/7）的p16阳性肿瘤患者为高分期（2例II期，3例III期和1例IV期），5例DOD。除一名患者外，所有这些患者的肿瘤也有p53过表达。所有3例患者均患有Her-2过表达DOD（I、III和IV期）。结论：3级EEC与低级别EEC一样，cyclin D1过表达但不扩增，Her-2过表达和扩增频率低。3级EEC与SC共享相对常见的p53和p16过表达和低频率的错配修复基因丢失。然而，与通常显示WT-1、细胞周期蛋白D1扩增和Her-2过表达和/或扩增的SC EC相反，3级EC很少过表达任何这些标志物。此外，在这项研究中，显示MLH-1/MSH-2或细胞周期蛋白D1过表达缺失的肿瘤患者更可能患有低分期肿瘤（I期），而过表达p53、p16或Her-2的肿瘤患者通常与高分期肿瘤相关。
Two types of endometrial carcinoma (EC) have been delineated on the basis of clinicopathologic studies. Low-grade endometrioid carcinoma (EEC) is the prototype of type I EC and is characterized by microsatellite instability and PTEN, K-ras, and/or beta-catenin gene mutations, whereas type II EC is typically represented by serous and clear cell carcinomas (SCs/CCCs), the former frequently showing p53 mutations and c-erb-2 overexpression; however, the molecular profile of grade 3 EEC has not yet been well characterized. The goal of this study was to define the immunohistochemical and molecular profile of grade 3 EEC. We studied 25 patients with grade 3 EEC ranging in age from 35 to 87 (mean 61) years. At the time of initial diagnosis, 16 patients had stage I tumors, whereas 3, 5, and 1 had stages II, III, and IV tumors, respectively. Only 1 patient with stage IV tumor had disease in the peritoneum because of direct extend of tumor through the uterine wall. Two tissue microarrays were constructed from paraffin-embedded blocks and stained for MLH-1, MSH-2, p16, cyclin D1, C-erb-B2, WT-1, and p53. Loss of MLH-1 and MSH-2 was seen in 3 of 25 and 1 of 24 tumors, respectively; none showed loss of both. Diffuse p16 nuclear expression was found in 7 of 23 cases; diffuse and strong nuclear immunostaining for p53, cyclin D1, and Her-2 was seen in 9 of 24 neoplasms, 9 of 25, and 3 of 25 carcinomas, respectively. WT-1 was negative in all 25 tumors. One of the 3 grade 3 EECs with Her-2 overexpression showed gene amplification by fluorescence in situ hybridization analysis. No gene amplification for cyclin D1 was found. Followup information was available for all patients. Sixteen had stage I tumors. Of these patients, 11 were alive and well (AW), 3 died of disease (DOD), and 2 died of unrelated causes (DUC), with a mean follow-up time of 56 months (range, 24 to 96 mo); 2 of 3 patients with stage II tumors DOD, and 1 was AW with a mean follow-up time of 81 months (range, 6 to 66 mo); of the 5 patients with stage III tumors, 2 DOD, 1 was AW, 1 was alive with lung metastases, and 1 DUC [mean follow-up of 29 months (range, 12 to 74 mo)]; the only patient who had a stage IV tumor DOD 12 months later. Interestingly, patients with grade 3 EECs showing loss of MLH-1/MSH-2 had stage I tumors, and all were AW (60 to 84 mo). Seventy-seven percent (7 of 9) of patients with tumors showing cyclin D1 overexpression were stage I, and none died of disease, whereas 85% (6 of 7) of patients with p16-positive tumors were high stage (2 stage II, 3 stage III, and 1 stage IV), and 5 DOD. All but one of these patients had tumors that also had p53 overexpression. All 3 patients with Her-2 overexpression DOD (stages I, III, and IV). In conclusion, this study shows that grade 3 EEC shares with low-grade EEC the overexpression but not amplification of cyclin D1 and low frequency of Her-2 overexpression and amplification. Grade 3 EEC shares with SC the relatively common p53 and p16 overexpression and low frequency of loss of mismatch repair genes. However, in contrast to SC ECs, which often show WT-1, cyclin D1 amplification, and Her-2 overexpression and/or amplification, grade 3 EECs rarely overexpressed any of these markers. Moreover, in this study, patients with tumors showing loss of MLH-1/MSH-2 or cyclin D1 overexpression were more likely to have low-stage tumors (stage I), whereas patients with tumors that overexpressed p53, p16, or Her-2 were frequently associated with high-stage tumors.