PMID- 37565303 OWN - NLM STAT- MEDLINE DCOM- 20231005 LR - 20231005 IS - 1365-2559 (Electronic) IS - 0309-0167 (Linking) VI - 83 IP - 5 DP - 2023 Nov TI - Loss of YAP1 C-terminus expression as an ancillary marker for metaplastic thymoma: a potential pitfall in detecting YAP1::MAML2 gene rearrangement. PG - 798-809 LID - 10.1111/his.15024 [doi] AB - AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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. CI - (c) 2023 John Wiley & Sons Ltd. FAU - Wang, Xuan AU - Wang X AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Liu, Lei-Lei AU - Liu LL AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Li, Qing AU - Li Q AD - Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, China. FAU - Xia, Qiu-Yuan AU - Xia QY AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Li, Rui AU - Li R AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Ye, Sheng-Bing AU - Ye SB AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Zhang, Ru-Song AU - Zhang RS AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Fang, Ru AU - Fang R AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Chen, Hui AU - Chen H AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Wu, Nan AU - Wu N AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. FAU - Rao, Qiu AU - Rao Q AUID- ORCID: 0000-0002-2674-1937 AD - Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. LA - eng GR - 82273327/National Natural Science Foundation of China/ GR - 82103192/National Natural Science Foundation of China/ PT - Journal Article DEP - 20230811 PL - England TA - Histopathology JT - Histopathology JID - 7704136 RN - 0 (Transcription Factors) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (MAML2 protein, human) RN - 0 (Trans-Activators) SB - IM MH - Humans MH - *Thymoma/diagnosis/genetics/metabolism MH - In Situ Hybridization, Fluorescence MH - Transcription Factors/genetics/metabolism MH - *Thymus Neoplasms/diagnosis/genetics/metabolism MH - Adaptor Proteins, Signal Transducing/genetics MH - Gene Rearrangement MH - Trans-Activators/genetics OTO - NOTNLM OT - MAML2 OT - YAP1 OT - gene rearrangement OT - metaplastic thymoma EDAT- 2023/08/11 06:42 MHDA- 2023/10/05 06:43 CRDT- 2023/08/11 04:33 PHST- 2023/07/11 00:00 [revised] PHST- 2023/05/09 00:00 [received] PHST- 2023/07/21 00:00 [accepted] PHST- 2023/10/05 06:43 [medline] PHST- 2023/08/11 06:42 [pubmed] PHST- 2023/08/11 04:33 [entrez] AID - 10.1111/his.15024 [doi] PST - ppublish SO - Histopathology. 2023 Nov;83(5):798-809. doi: 10.1111/his.15024. Epub 2023 Aug 11.