Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup
Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup
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DOI：
10.1097/pas.0000000000000764
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发表时间：
2017-02-01
影响因子：
5.6
通讯作者：
Gilks, C. Blake
中科院分区：
文献类型：
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作者：
Hoang, Lien N.;Kinloch, Mary A.;Gilks, C. Blake
癌症基因组图谱最近确定了基于基因组的子宫内膜癌分子分类，分为 4 种分子类别：(1) 超突变（聚合酶 epsilon [POLE] 突变）、(2) 超突变（微卫星不稳定性）、(3) 低拷贝数异常和 (4) 高拷贝数异常。此后，两项研究提出了将子宫内膜癌分为 4 个分子亚组的模型，以癌症基因组图谱为模型，使用简化且更临床适用的替代方法。在我们的研究中，使用 POLE 核酸外切酶结构域突变 (EDM) 测序以及 p53 和错配修复 (MMR) 蛋白的免疫组织化学对 151 例子宫内膜癌进行了分子分类。这将病例分为 4 组中的 1 组：(1) POLE EDM、(2) MMR-D、(3) p53 野生型 (p53 wt) 或 (4) p53 异常 (p53 abn)。七名妇科病理学家被要求将每个病例分配到以下类别之一：1 至 2 级子宫内膜样癌 (EC)、3 级 EC、粘液癌、浆液性癌 (SC)、透明细胞癌、去分化癌、癌肉瘤、混合癌和其他。所有 7 名病理学家的共识诊断在 p53 wt 组中最高（37/41，90%），在 p53 abn 组中最低（14/36，39%），在 POLE EDM 组（22/34，65%）和 MMR-D 组（23/40，58%）中居于中间。尽管大多数 p53 wt 子宫内膜癌为 1 至 2 级 EC（敏感性：90%），但只有不到一半的 1 至 2 级 EC 属于 p53 wt 类别（阳性预测值：42%）。纯 SC 几乎总是属于 p53 abn 组（阳性预测值：96%），但作为 p53 abn 的标记物不敏感（敏感性 64%），并且诊断 SC 的再现性欠佳。子宫内膜癌精确组织学分类的局限性凸显了辅助分子分类方案的重要性。
The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLE EDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLE EDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme.