Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
Histopathology. 2023 Nov;83(5):798-809. doi: 10.1111/his.15024. Epub 2023 Aug 11.
Metaplastic thymoma is a rare thymic tumour characterized by Yes Associated Protein 1 (YAP1) and Mastermind Like Transcriptional Coactivator 2 (MAML2) gene fusions resulting from an intrachromosomal inversion of chromosome 11. Immunohistochemistry with an antibody directed against the C-terminus of YAP1 has shown loss of expression in YAP1-rearranged vascular neoplasms, poromas, and porocarcinomas. This study aimed to validate an anti-YAP1 C-terminal antibody as an ancillary immunohistochemical marker for the diagnosis of metaplastic thymoma.
Ten metaplastic thymomas were selected for the current study. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed to detect YAP1::MAML2 fusions. We then performed immunohistochemistry to detect YAP1 C-terminus expression in 10 metaplastic thymomas, 50 conventional thymomas (10 each of type A thymoma, type AB thymoma, type B1 thymoma, type B2 thymoma, and type B3 thymoma) and seven thymic carcinomas.
All 10 cases showed narrow split signals with a distance of nearly two signal diameters and sometimes had false-negative results in YAP1 and MAML2 break-apart FISH (BA-FISH). Abnormal colocalized signals of the YAP1::MAML2 fusion were observed in all 10 cases using fusion FISH (F-FISH) assays. Eight of 10 cases with adequate nucleic acids were successfully sequenced and all showed YAP1::MAML2 fusions; in two cases the fusions were detected by both DNA and RNA sequencing and in six cases by RNA sequencing only. YAP1::MAML2 fusion transcripts were identified in four cases by RT-PCR. Metaplastic thymoma showed loss of YAP1 C-terminus expression in all 10 (100%) cases. All other thymic neoplasms showed retained YAP1 C-terminus expression.
YAP1 C-terminus immunohistochemistry is a highly sensitive and specific ancillary marker that distinguishes metaplastic thymoma from its mimics. BA-FISH assays could not effectively detect YAP1::MAML2 fusions due to the proximity of the two genes. Loss of YAP1 C-terminus expression is a reliable surrogate for the detection of YAP1::MAML2 fusions in metaplastic thymoma.
具有间变性特征的胸腺瘤是一种罕见的胸腺肿瘤，其特征在于 Yes 相关蛋白 1 (YAP1) 和主转录因子样转录共激活因子 2 (MAML2) 基因融合，这是由于 11 号染色体的染色体内倒位所致。针对 YAP1 C 末端的免疫组化抗体检测已显示 YAP1 重排的血管肿瘤、汗孔瘤和汗孔癌中 YAP1 表达缺失。本研究旨在验证针对 YAP1 C 末端的抗体作为辅助免疫组化标志物，用于诊断具有间变性特征的胸腺瘤。
选择了 10 例具有间变性特征的胸腺瘤用于本研究。通过荧光原位杂交 (FISH)、下一代测序 (NGS) 和逆转录-聚合酶链反应 (RT-PCR) 分析检测 YAP1::MAML2 融合。然后，我们对 10 例具有间变性特征的胸腺瘤、50 例常规胸腺瘤（10 例 A 型胸腺瘤、10 例 AB 型胸腺瘤、10 例 B1 型胸腺瘤、10 例 B2 型胸腺瘤和 10 例 B3 型胸腺瘤）和 7 例胸腺癌进行了 YAP1 C 末端表达的免疫组化检测。
所有 10 例均显示出狭窄的分裂信号，距离近两个信号直径，有时 YAP1 和 MAML2 分离 FISH (BA-FISH) 检测呈假阴性。所有 10 例均通过融合 FISH (F-FISH) 检测到 YAP1::MAML2 融合的异常共定位信号。8 例具有足够核酸的病例成功进行了测序，所有病例均显示 YAP1::MAML2 融合；在 2 例病例中，融合通过 DNA 和 RNA 测序检测到，在 6 例病例中仅通过 RNA 测序检测到。通过 RT-PCR 在 4 例病例中鉴定出 YAP1::MAML2 融合转录本。所有 10 例具有间变性特征的胸腺瘤（100%）均显示 YAP1 C 末端表达缺失。所有其他胸腺肿瘤均显示 YAP1 C 末端表达保留。
YAP1 C 末端免疫组化是一种高度敏感和特异的辅助标志物，可将具有间变性特征的胸腺瘤与其他模拟物区分开来。BA-FISH 检测因两个基因的接近而不能有效检测 YAP1::MAML2 融合。YAP1 C 末端表达缺失是检测具有间变性特征的胸腺瘤中 YAP1::MAML2 融合的可靠替代物。
