Objective: To investigate the clinicopathological features, and molecular genetic alterations of metaplastic thymoma (MT). Methods: A total of ten MT cases, diagnosed from 2011 to 2021, were selected from the Department of Pathology of Jinling Hospital, Nanjing University Medical School, Nanjing, China for clinicopathological and immunohistochemical (IHC) examination and clinical follow-up. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and YAP1 C-terminus (YAP1-CT) IHC were performed to detect YAP1::MAML2 fusions. Results: There were four males and six females, ranging in age from 29 to 60 years (mean 50 years, median 54 years). Microscopically, all tumors showed a typical biphasic morphology consisting of epithelial components and gradually or abruptly transitioning spindle cell components. The two components were present in varying proportions in different cases. Immunophenotypically, the epithelial cells were diffusely positive for CKpan, CK5/6 and p63. The spindle cells were diffusely positive for vimentin and focally positive for EMA. TdT was negative in the background lymphocytes. Ki-67 proliferation index was less than 5%. YAP1 and MAML2 break-apart FISH analyses showed that all ten cases had narrow split signals with a distance of nearly 2 signal diameters and may be considered false-negative. Using YAP1::MAML2 fusion FISH assays, abnormal fusion signals were observed in all the ten cases. NGS demonstrated YAP1::MAML2 fusions in all eight cases with adequate nucleic acids; in two cases the fusions were detected by DNA sequencing and in eight cases by RNA sequencing. All ten cases of MT demonstrated loss of YAP1 C-terminal expression in epithelioid cells. Conclusions: MT is a rare and low-grade thymic tumor characterized by a biphasic pattern and YAP1::MAML2 fusions. Break-apart FISH assays may sometimes show false-negative results due to the proximity of YAP1 and MAML2, while YAP1 C-terminal IHC is a highly sensitive and specific marker for MT. Loss of YAP1 C-terminal expression can also be used to screen YAP1::MAML2 fusions for possible MT cases.
目的： 探讨化生性胸腺瘤（metaplastic thymoma，MT）的临床病理学特征、分子遗传学特征及检测策略。 方法： 对解放军东部战区总医院病理科2011—2021年诊断的10例MT进行光镜观察、免疫组织化学染色及随访，并采用荧光原位杂交（FISH）、二代测序和C-末端YAP1抗体（YAP1-CT）检测MT中的YAP1：：MAML2基因融合。 结果： 10例患者中男性4例，女性6例。患者年龄29~60岁，平均年龄50岁，中位年龄54岁。镜下肿瘤表现为特征性的双相结构，由上皮细胞和梭形细胞组成，2种成分突然转化或逐渐过渡，并且在不同病例中比例变化很大。免疫表型：上皮细胞广谱细胞角蛋白（CKpan）、细胞角蛋白（CK）5/6、p63均弥漫阳性；梭形细胞波形蛋白弥漫阳性，上皮细胞膜抗原（EMA）局灶阳性；间质淋巴细胞末端脱氧核苷酸转移酶（TdT）阴性；Ki-67阳性指数均<5%。YAP1和MAML2分离FISH结果显示，10例MT中均可见间隔较小且距离接近2个信号宽度的分离信号，可能被误判为阴性。采用YAP1：：MAML2融合FISH检测，10例MT均观察到异常的融合信号。二代测序显示，8例组织足够的病例均检测到YAP1：：MAML2融合基因，其中DNA测序检测出2例，RNA测序检测出8例。YAP1-CT在所有10例MT的上皮细胞中均表达缺失。 结论： MT是一种罕见的低度恶性的胸腺肿瘤，具有特征性的双相结构和YAP1：：MAML2融合。由于YAP1和MAML2这两个基因相距较近，分离FISH结果可能被误判为阴性。YAP1-CT是诊断MT高度灵敏和特异的标志物，其表达缺失可用于MT中YAP1：：MAML2融合的筛查。.