透明透明细胞癌(HCCC)是一种罕见的小唾液腺起源的惰性恶性肿瘤,具有EWSR1::ATF1重排。病理上,肿瘤细胞在透明基质的背景下具有清晰的细胞质。一般来说,肿瘤细胞p63和p40阳性,s100和α-平滑肌肌动蛋白阴性,表明它们分化成鳞状上皮而不是肌上皮。在这项研究中,我们对6例HCCC进行了详细的组织病理学和基因组分析,包括2种非典型亚型-1例“高级转化”和1例具有EWSR1的新伴侣基因。“我们通过全外显子组测序对原发性和复发性肿瘤进行了序贯分析,RNA测序,桑格测序,和荧光原位杂交来研究基因组变化对组织病理学和临床预后的影响。在所有情况下都检测到涉及EWSR1基因的融合基因。五个案例,包括“高等级改造”,“拥有一个已知的EWSR1::ATF1融合基因;然而,1例携带一个新的EWSR1::LARP4融合基因。这种新的EWSR1::LARP4融合的HCCC具有SOX10阳性染色,这与EWSR1::ATF1融合的HCCC不同。根据全外显子组测序和荧光原位杂交分析,涉及CDKN2A的“全基因组加倍”和局灶性缺失,CDKN2B,在具有高级转化的HCCC中检测到PTEN。“最后,我们在惰性HCCC中鉴定了EWSR1的新伴侣基因LARP4。重要的是,“高级转化”和不良预后是由全基因组加倍和随后的基因组畸变引起的。
Hyalinizing clear cell carcinoma (HCCC) is a rare indolent malignant tumor of minor salivary gland origin with EWSR1::ATF1 rearrangement. Pathologically, the tumor cells possess a clear cytoplasm in a background of hyalinized stroma. Generally, the tumor cells are positive for p63 and p40 and negative for s100 and α-smooth muscle actin, suggesting that they differentiate into squamous epithelium and not into myoepithelium. In this study, we performed a detailed histopathological and genomic analysis of 6 cases of HCCC, including 2 atypical subtypes-a case of \"high-grade transformation\" and 1 \"possessing a novel partner gene for EWSR1.\" We performed a sequential analysis of the primary and recurrent tumor by whole-exome sequencing, RNA sequencing, Sanger sequencing, and fluorescence in situ hybridization to investigate the effect of genomic changes on histopathology and clinical prognosis. A fusion gene involving the EWSR1 gene was detected in all cases. Five cases, including the \"high-grade transformation,\" harbored a known EWSR1::ATF1 fusion gene; however, 1 case harbored a novel EWSR1::LARP4 fusion gene. This novel EWSR1::LARP4-fused HCCC has a SOX10-positive staining, which is different from the EWSR1::ATF1-fused HCCC. According to whole-exome sequencing and fluorescence in situ hybridization analysis, the \"whole-genome doubling\" and focal deletion involving CDKN2A, CDKN2B, and PTEN were detected in HCCC with \"high-grade transformation.\" Conclusively, we identified a novel partner gene for EWSR1, LARP4, in indolent HCCC. Importantly, \"high-grade transformation\" and poor prognosis were caused by whole-genome doubling and subsequent genomic aberrations.