Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Lung Cancer. 2017 Feb;104:98-105. doi: 10.1016/j.lungcan.2016.12.017. Epub 2016 Dec 23.
Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16 (p16) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique. Thus, we sought to develop a IHC-based method that could predict the deletion of p16 in MPM in concordance with 9p21 FISH.
We examined the expression of the 9p21.3-related proteins (p14, p15, p16, and methylthioadenosine phosphorylase (MTAP)) and BAP1 using IHC in 51 MPM and 25 RMH cases, and assessed their correlation with HD of p16 detected by FISH. The diagnostic usefulness of IHC of the 9p21.3-related proteins and BAP1 and their combinations was assessed using the cut-off values set by receiver operating characteristic (ROC) analysis.
Among the 9p21.3-related proteins, MTAP IHC findings showed best concordance with 9p21 FISH results (kappa coefficient of 0.69) and a specificity of 100%. We also examined the combinations of MTAP IHC with the other products. The loss of p16 and MTAP had better concordance (kappa coefficient of 0.71), although lower specificity (85%). For differentiating MPM from RMH, only MTAP showed 100% specificity among the 9p21.3-related proteins, as did BAP1 IHC and 9p21 FISH. Among BAP1 combinations, only that of BAP1 with MTAP showed 100% specificity. Its sensitivity was 76.5%, which was lower than BAP1 IHC and 9p21 FISH combination (84.3%), but higher than BAP1 IHC alone (60.8%) or 9p21 FISH alone (60.8%).
A combination of MTAP or BAP1 loss detected by IHC can likely detect MPM with good sensitivity and 100% specificity, and serve as useful ancillary IHC for discriminating MPM from RMH.
区分恶性胸膜间皮瘤（MPM）和反应性间皮增生（RMH）仍然具有挑战性。荧光原位杂交（FISH）检测 9p21 区域的纯合缺失（HD），包括 p16（p16），以及免疫组化检测 BRCA1 相关蛋白 1（BAP1）缺失，是 MPM 诊断的可靠标志物。然而，并非所有实验室都具备进行 9p21 FISH 的条件；免疫组化（IHC）是一种更为常见且可行的技术。因此，我们试图开发一种基于 IHC 的方法，该方法可以预测 MPM 中 p16 的缺失情况，与 9p21 FISH 结果一致。
我们在 51 例 MPM 和 25 例 RMH 病例中，使用 IHC 检测了 9p21.3 相关蛋白（p14、p15、p16 和甲基硫腺苷磷酸化酶（MTAP））和 BAP1 的表达情况，并评估了它们与 FISH 检测到的 p16 HD 的相关性。使用受试者工作特征（ROC）分析设定的截止值评估 9p21.3 相关蛋白和 BAP1 的 IHC 及其组合的诊断效用。
在 9p21.3 相关蛋白中，MTAP IHC 结果与 9p21 FISH 结果的一致性最佳（kappa 系数为 0.69），特异性为 100%。我们还检查了 MTAP IHC 与其他产物的组合。p16 和 MTAP 的缺失具有更好的一致性（kappa 系数为 0.71），尽管特异性较低（85%）。在区分 MPM 和 RMH 方面，9p21.3 相关蛋白中只有 MTAP 具有 100%的特异性，BAP1 IHC 和 9p21 FISH 也是如此。在 BAP1 组合中，只有 BAP1 与 MTAP 的组合具有 100%的特异性。其灵敏度为 76.5%，低于 BAP1 IHC 和 9p21 FISH 组合（84.3%），但高于 BAP1 IHC 单独（60.8%）或 9p21 FISH 单独（60.8%）。
通过 IHC 检测到的 MTAP 或 BAP1 缺失可能具有良好的灵敏度和 100%的特异性，有助于区分 MPM 和 RMH，可作为有用的辅助 IHC 方法。
