Rhee Hyungjin, Kim Haeryoung, Park Young Nyun
Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Liver Cancer. 2020 Dec;9(6):663-681. doi: 10.1159/000510522. Epub 2020 Oct 23.
Hepatocellular carcinoma (HCC) is a heterogeneous neoplasm, both from the molecular and histomorphological aspects. One example of heterogeneity is the expression of keratin 19 (K19) in a subset (4-28%) of HCCs. The presence of K19 expression in HCCs has important clinical implications, as K19-positive HCCs have been associated with aggressive tumor biology and poor prognosis. Histomorphologically, K19-positive HCCs demonstrate a more infiltrative appearance, poor histological differentiation, more frequent vascular invasion, and more intratumoral fibrous stroma than K19-negative conventional HCCs. From the molecular aspect, K19-positive HCCs have been matched with various gene signatures that have been associated with stemness and poor prognosis, including the G1-3 groups, S2 class, cluster A, proliferation signature, and vascular invasion signature. K19-positive HCCs also show upregulated signatures related to transforming growth factor-β pathway and epithelial-to-mesenchymal transition. The main regulators of K19 expression include hepatocyte growth factor-MET paracrine signaling by cancer-associated fibroblast, epidermal growth factor-epidermal growth factor receptor signaling, laminin, and DNA methylation. Clinically, higher serum alpha-fetoprotein levels, frequent association with chronic hepatitis B, more invasive growth, and lymph node metastasis have been shown to be characteristics of K19-positive HCCs. Radiologic features including atypical enhancement patterns, absence of tumor capsules, and irregular tumor margins can be a clue for K19-positive HCCs. From a therapeutic standpoint, K19-positive HCCs have been associated with poor outcomes after curative resection or liver transplantation, and resistance to systemic chemotherapy and locoregional treatment, including transarterial chemoembolization and radiofrequency ablation. In this review, we summarize the currently available knowledge on the clinico-radio-pathological and molecular features of K19-expressing HCCs, including a detailed discussion on the regulation mechanism of these tumors.
肝细胞癌（HCC）在分子和组织形态学方面都是一种异质性肿瘤。异质性的一个例子是角蛋白19（K19）在一部分（4%-28%）HCC中的表达。HCC中K19表达的存在具有重要的临床意义，因为K19阳性的HCC与侵袭性肿瘤生物学行为和不良预后相关。在组织形态学上，与K19阴性的传统HCC相比，K19阳性的HCC表现出更具浸润性的外观、较差的组织学分化、更频繁的血管侵犯以及更多的瘤内纤维间质。从分子方面来看，K19阳性的HCC与多种与干性和不良预后相关的基因特征相匹配，包括G1-3组、S2类、A簇、增殖特征和血管侵犯特征。K19阳性的HCC还显示出与转化生长因子-β途径和上皮-间质转化相关的上调特征。K19表达的主要调节因子包括癌相关成纤维细胞的肝细胞生长因子-MET旁分泌信号、表皮生长因子-表皮生长因子受体信号、层粘连蛋白和DNA甲基化。临床上，较高的血清甲胎蛋白水平、常与慢性乙型肝炎相关、更具侵袭性的生长以及淋巴结转移已被证明是K19阳性HCC的特征。包括非典型强化模式、无肿瘤包膜和不规则肿瘤边缘在内的放射学特征可能是K19阳性HCC的一个线索。从治疗角度来看，K19阳性的HCC在根治性切除或肝移植后预后较差，并且对全身化疗和局部治疗（包括经动脉化疗栓塞和射频消融）耐药。在这篇综述中，我们总结了目前关于K19表达的HCC的临床-放射-病理和分子特征的现有知识，包括对这些肿瘤调节机制的详细讨论。
