Cyrta Joanna, Masliah-Planchon Julien, Hoare Owen, Brillet Riwan, Andrianteranagna Mamy, Sohier Pierre, Cardoen Liesbeth, Bouchoucha Yassine, Filser Mathilde, Goncalves Andreia, Caly Martial, Fréneaux Paul, Stefanaki Kalliopi, Pefkianaki Maria, Moschovi Maria, Matet Alexandre, Cassoux Nathalie, Lumbroso-Le Rouic Livia, Gauthier-Villars Marion, Stern Marc-Henri, Vincent-Salomon Anne, Rodrigues Manuel, Bourdeaut Franck
Department of Pathology, Institut Curie, PSL Research University, Paris, France.
Department of Genetics, Institut Curie, PSL Research University, Paris, France.
J Pathol. 2025 Mar;265(3):357-371. doi: 10.1002/path.6390. Epub 2025 Jan 23.
Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
横纹肌样瘤（RT）是一种侵袭性恶性肿瘤，影响2岁以下婴儿，几乎所有病例的特征是SWI/SNF相关BAF染色质重塑复合体亚基B1（SMARCB1）发生双等位基因功能丧失改变。约30%的患者存在种系SMARCB1改变，并定义了1型RT易感性综合征（RTPS1）。葡萄膜黑色素瘤（UVM）是成人中最常见的原发性眼内癌，不存在SMARCB1改变。我们报告了两例以前未描述的眼内恶性肿瘤病例，它们与UVM和RT有一些共同特征，但也与这些实体不同。两名女性患者，年龄分别为23岁和14岁，均接受了眼球摘除术，并对肿瘤进行了全面的基因组、DNA甲基化和转录组分析。病理检查显示为具有上皮样特征的大型无色素眼内肿瘤，免疫组化（IHC）显示表达黑素细胞标志物[S100P、SOX10、Melan-A、PMEL（HMB45）、TYR]，但黑色素生成很少或没有。两种肿瘤均存在双等位基因功能丧失的SMARCB1改变，与IHC上SMARCB1（BAF47/INI1）表达缺失相关。它们的基因组图谱对于UVM和RT来说都是非典型的，在其他检测基因中未发现致病变异，包括在UVM中经常发生改变的基因。在两名患者中均发现了种系SMARCB1变异。然而，没有相关的癌症家族史。转录组和甲基化组分析表明，这些肿瘤与RT、UVM和皮肤黑色素瘤不同。RNA测序证实了与黑素细胞分化相关的早期和晚期基因的表达。第一名患者在诊断后16个月死于转移性疾病，第二名患者在完成治疗后10个月无疾病。总之，我们报告了两例以前未描述的、具有黑素细胞分化的侵袭性SMARCB1缺陷型眼内恶性肿瘤病例，该肿瘤发生于年轻患者，与UVM和RT不同，并扩展了RTPS1谱。© 2025作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
