Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases.
Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases.
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DOI：
10.1097/pas.0000000000001656
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发表时间：
2021-05-01
期刊：
影响因子：
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通讯作者：
Antonescu CR
中科院分区：
文献类型：
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作者：
Argani P;Lian DWQ;Agaimy A;Metzler M;Wobker SE;Matoso A;Epstein JI;Sung YS;Zhang L;Antonescu CR
儿科间皮瘤很少见，其发病机制尚不清楚。在这项研究中，我们报告了5例儿童恶性间皮瘤，其特点是融合涉及间变性淋巴瘤激酶（ALK）基因。4例病例发生在涉及腹腔的女性中，其特征为纯上皮样形态。第五个出现在图尼卡迷走神经的一个15岁的男性和显示双相上皮样肉瘤样表型。所有病例均表现出典型的恶性间皮瘤的形态学和免疫组化特征，包括管状乳头状结构和立方上皮样细胞，细胞浆嗜酸性，细胞核均匀，染色质呈泡状。免疫组化显示，所有病例均标记ALK、细胞角蛋白、WT-1和钙视黄蛋白，但缺乏腺癌免疫标记物的表达。4例病例显示PAX 8蛋白的弱-中度标记，这导致原发性腹膜浆液性癌的诊断挑战。通过组合分子方法研究ALK遗传异常。在2例病例中进行了Archer融合，显示ALK与STRN或TPM 1基因之间的融合，产生了保留ALK激酶结构域的转录本。1例通过DNA靶向测序进一步研究，但未观察到额外的遗传改变。在1例病例中，细胞遗传学分析显示存在t（2;15）（p23;q22），FISH证实ALK基因断裂。在其余2例病例中，通过FISH证实ALK基因重排。与与石棉暴露密切相关的成人间皮瘤不同，通常表现出BAP 1表达的缺失并具有复杂的核型，ALK重排间皮瘤似乎与其他融合阳性间皮瘤相似，例如具有EWSR 1/FUS-ATF 1融合的间皮瘤，具有显著的形态学重叠，发生在年轻患者中，并显示出简单的易位驱动的遗传特征。
Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT-1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In one case cytogenetic analysis showed the presence of a t(2;15)(p23;q22), and FISH confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by FISH. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion positive-mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.