Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy.
Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy.
Acta Obstet Gynecol Scand. 2018 Dec;97(12):1415-1426. doi: 10.1111/aogs.13452. Epub 2018 Oct 11.
Endometrial hyperplasia is differentiated into benign or premalignant. Two histological classifications are used for this purpose: World Health Organization (WHO) classification, based on cytological atypia, disregarding glandular complexity, and endometrial intraepithelial neoplasia (EIN) classification, based on several different parameters. B-cell lymphoma 2 (Bcl-2) loss has been studied as immunohistochemical marker with the aim of improving the differential diagnosis between benign and premalignant hyperplasia. We aimed to evaluate: (A) Bcl-2 loss as marker of endometrial precancer, by assessing it in proliferative endometrium, benign hyperplasia, premalignant hyperplasia, and endometrial cancer; (B) the diagnostic accuracy of Bcl-2 in the differential diagnosis between benign and premalignant endometrial hyperplasia; (c) how the results change according to the histological classification and the thresholds of Bcl-2 expression used.
Electronic databases were searched from their inception to March 2018. All studies assessing Bcl-2 immunohistochemistry in endometrial specimens were included.
In total, 20 observational studies assessing 1,278 specimens were included. Bcl-2 loss rates were not significantly different between proliferative endometrium and benign hyperplasia (P = 0.12) and between premalignant hyperplasia and endometrial cancer (P = 0.53). Among hyperplasias, Bcl-2 loss was significantly associated with premalignancy, according to both the WHO (OR = 4.39; P < 0.00001) and EIN classifications (OR = 6.07; P = 0.01), and also with architecture complexity (OR = 2.06; P = 0.02). Using the WHO classification, Bcl-2 loss showed low diagnostic accuracy in detecting premalignant hyperplasia (area under the curve [AUC] = 0.708), with a sensitivity of 0.41, a specificity of 0.81, a positive likelihood ratio of 3.22, and a negative likelihood ratio of 0.69. Using the EIN classification, accuracy was high (AUC = 0.938), with a sensitivity of 0.18, a specificity of 0.97, a positive likelihood ratio of 5.16 and a negative likelihood ratio of 0.86. Thresholds of Bcl-2 expression not involving a complete loss showed lower diagnostic accuracy with a slight increase in sensitivity, but a severe decrease in specificity.
B-cell lymphoma 2 loss is a marker of endometrial precancer, with a high specificity and high diagnostic accuracy if the EIN classification is used. Thresholds of Bcl-2 expression not involving a complete loss should not be considered. Bcl-2 loss in endometrial hyperplasia may be a novel indication for treatment when precancerous features are ambiguous in a histological examination. Bcl-2 loss correlates better with EIN classification than with the WHO classification, suggesting that glandular complexity is an important precancerous feature.
子宫内膜增生分为良性或癌前病变。为此目的使用两种组织学分类：基于细胞学异型性、不考虑腺体复杂性的世界卫生组织（WHO）分类，和基于几个不同参数的子宫内膜上皮内肿瘤（EIN）分类。B 细胞淋巴瘤 2（Bcl-2）缺失已作为免疫组化标志物进行研究，目的是改善良性和癌前增生之间的鉴别诊断。我们旨在评估：（A）Bcl-2 缺失作为子宫内膜癌前病变的标志物，通过评估增生期子宫内膜、良性增生、癌前增生和子宫内膜癌中的 Bcl-2 缺失；（B）Bcl-2 在良性和癌前子宫内膜增生的鉴别诊断中的诊断准确性；（c）根据使用的组织学分类和 Bcl-2 表达的阈值，结果如何变化。
从其开始到 2018 年 3 月，检索电子数据库。所有评估子宫内膜标本中 Bcl-2 免疫组化的研究均包括在内。
总共纳入了 20 项观察性研究，评估了 1278 个标本。在增生期子宫内膜和良性增生之间（P=0.12）以及在癌前增生和子宫内膜癌之间（P=0.53），Bcl-2 缺失率无显著差异。在增生症中，根据 WHO（OR=4.39；P<0.00001）和 EIN 分类（OR=6.07；P=0.01），Bcl-2 缺失与癌前病变显著相关，也与结构复杂性（OR=2.06；P=0.02）相关。使用 WHO 分类，Bcl-2 缺失在检测癌前增生时显示出低诊断准确性（曲线下面积[AUC]为 0.708），敏感性为 0.41，特异性为 0.81，阳性似然比为 3.22，阴性似然比为 0.69。使用 EIN 分类，准确性较高（AUC=0.938），敏感性为 0.18，特异性为 0.97，阳性似然比为 5.16，阴性似然比为 0.86。不涉及完全缺失的 Bcl-2 表达阈值的诊断准确性较低，敏感性略有增加，但特异性严重下降。
B 细胞淋巴瘤 2 缺失是子宫内膜癌前病变的标志物，如果使用 EIN 分类，具有高特异性和高诊断准确性。不应该考虑不涉及完全缺失的 Bcl-2 表达阈值。在组织学检查中癌前特征不明确时，子宫内膜增生中的 Bcl-2 缺失可能是治疗的新指征。Bcl-2 缺失与 EIN 分类的相关性优于与 WHO 分类的相关性，这表明腺体复杂性是一个重要的癌前特征。
