Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Department of Pathology, Kyorin University Hospital, Tokyo, Japan.
Virchows Arch. 2019 Jan;474(1):39-46. doi: 10.1007/s00428-018-2476-0. Epub 2018 Oct 23.
Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.
嗜同性病毒整合位点 1 蛋白同源物 (EVI1) 是一种已知的造血细胞致癌转录因子，通过增加 KRAS 的表达促进胰腺癌的致癌性。由于 EVI1 在胆管癌中通过参考癌症基因组图谱而上调，我们研究了 EVI1 在肝内胆管癌 (ICC) 中的重要性，ICC 一直被认为是一组异质性癌症。免疫组织化学分析结果表明，大约一半的 ICC（53/101，52.5%）中 EVI1 过表达。此外，所有胆管内乳头状肿瘤病例无论组织学分级和亚型（胃型、肠型、胰胆管型或嗜酸细胞型）如何，均表达 EVI1（20/20，100%）。EVI1 阳性 ICC 具有更高频率的侵袭性病理指标，如管周浸润性生长（p=0.022）、肝门侵犯（p=0.041）、UICC 晚期（p=0.026）、主要血管侵犯（p=0.026）和神经周围侵犯（p=0.007），而非 EVI1 阴性 ICC。在所有切除病例和根治性切除病例中，EVI1 阳性 ICC 患者的总生存和无复发生存均较差。最近，我们根据粘蛋白产物和免疫表型（S100P、N-钙粘蛋白和 NCAM）提出了 ICC 的 1/2 型（大/小胆管型）分类。1 型主要由 EVI1 阳性 ICC 组成（42 例中的 33 例，79%），频率明显高于 2 型（55 例中的 18 例，32.7%）（p<0.0001）。EVI1 阳性 ICC 可能表达胃特异性紧密连接蛋白 CLDN18（相关系数 r=0.55373）和粘蛋白 MUC5AC（r=0.42718）。EVI1 阳性 ICC 是一种侵袭性 ICC，具有大胆管和/或胃表型。因此，转录因子 EVI1 与 ICC 的侵袭性行为相关，可作为治疗靶点分子，而 EVI1 可能是胆管内乳头状肿瘤发展的关键分子。
