Kervarrec Thibault, Macagno Nicolas, Houlier Aurelie, Pissaloux Daniel, Thamphya Brice, Louveau Baptiste, Mourah Samia, Mancini Maxence, Kazakov Dmitry, Harnisch Kim, Tirode Franck, Cazzato Gerardo, Sohier Pierre, de la Fouchardière Arnaud, Battistella Maxime, Calonje Eduardo
Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France.
"Biologie des Infections à Polyomavirus" Team, UMR INRA ISP 1282, Université de Tours, Tours, France.
Virchows Arch. 2025 Jul 21. doi: 10.1007/s00428-025-04175-6.
In 2019, YAP1::MAML2 and YAP1::NUTM1 rearrangements were demonstrated in the majority of poromas and in porocarcinomas. Recently, our group demonstrated recurrent fusions of PAK (p21 (RAC1) activated kinase) 1/2/3 genes in a subset of poromas and porocarcinomas frequently harboring hair follicle and sebaceous differentiation. To expand the spectrum of YAP1/PAK-fused tumors, we report six adnexal neoplasms with follicular differentiation with in frame YAP1::MAML2, YAP1::NUTM1, or RNF13::PAK2 fusion transcripts. Four cases of trichoblastoma and two neoplasms with panfollicular differentiation were included. Median age was 66 (range 39-76). Two patients were female. Tumors were located on the head (n = 4), chest (n = 1), or leg (n = 1). Microscopically, tumors were located in the dermis (n = 4) and/or subcutaneous tissue (n = 5), and showed macro (n = 6), micronodular (n = 5), and cystic (n = 4) structures. A delicate fibrillar stroma was present in 5 cases. Infundibulocystic structures, cell balls, and sebocytes were observed in 5, 1, and 3 cases, respectively. Immunohistochemistry revealed BerEP4 expression and Merkel cell hyperplasia in 5 and 2 cases, respectively. YAP1 (C-terminal) loss was observed in 5 cases. Accordingly YAP1::MAML2 (n = 2), YAP1::NUTM1 (n = 1), or RNF13::PAK2 (n = 1) inframe fusion transcripts were detected in the four trichoblastomas. YAP1::MAML2 fusions were also detected in the two tumors with panfollicular differentiation. In conclusion, we report six cases of follicular tumors with YAP1::MAML2, YAP1::NUTM1, or RNF13::PAK2 fusions and therefore suggest that in addition to poroid tumors, YAP1 and PAK2 fusions might be the oncogenic driver in a subset of adnexal tumors with prominent follicular differentiation.
2019年，在大多数汗孔瘤和汗孔癌中发现了YAP1::MAML2和YAP1::NUTM1重排。最近，我们团队在部分常伴有毛囊和皮脂腺分化的汗孔瘤和汗孔癌中发现了PAK（p21（RAC1）活化激酶）1/2/3基因的复发性融合。为了扩大YAP1/PAK融合肿瘤的范围，我们报告了6例具有滤泡分化的附属器肿瘤，其具有符合读框的YAP1::MAML2、YAP1::NUTM1或RNF13::PAK2融合转录本。其中包括4例毛母细胞瘤和2例具有全滤泡分化的肿瘤。中位年龄为66岁（范围39 - 76岁）。2例为女性。肿瘤位于头部（n = 4）、胸部（n = 1）或腿部（n = 1）。显微镜下，肿瘤位于真皮（n = 4）和/或皮下组织（n = 5），并呈现出大结节状（n = 6）、小结节状（n = 5）和囊性（n = 4）结构。5例可见纤细的纤维性间质。分别在5例、1例和3例中观察到漏斗状囊结构、细胞球和皮脂腺细胞。免疫组化显示，5例和2例分别有BerEP4表达和默克尔细胞增生。5例观察到YAP1（C端）缺失。相应地，在4例毛母细胞瘤中检测到YAP1::MAML2（n = 2）、YAP1::NUTM1（n = 1）或RNF13::PAK2（n = 1）符合读框的融合转录本。在2例具有全滤泡分化的肿瘤中也检测到YAP1::MAML2融合。总之，我们报告了6例具有YAP1::MAML2、YAP1::NUTM1或RNF13::PAK2融合的滤泡性肿瘤，因此表明除了类汗孔瘤外，YAP1和PAK2融合可能是一部分具有显著滤泡分化的附属器肿瘤的致癌驱动因素。
