Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence

Abstract

. Semiquantitative analysis of expression levels demonstrated a significant correlation between CK7 and CK19 expression. Of various clinicopathologic parameters, tumor differentiation exhibited a significant correlation with CK7 and CK19 expression. All 15 patients with CK19-positive HCC also had anti-HBc. Log-rank test revealed that CK7 expression, CK19 expression, high aspartate aminotransferase (AST) activity, low albumin concentration, portal invasion, intrahepatic metastasis, and severe fibrosis (cirrhosis) reduced the tumor-free survival rate. Multivariate analysis demonstrated that CK19 expression, intrahepatic metastasis, and severe fibrosis were independent predictors of postoperative recurrence, while CK7 expression was not. Twelve of 15 patients with CK19-positive HCC had tumor recurrence within 2 years after surgery, a significantly higher incidence of early recurrence than for CK19-negative HCC. The incidence of extrahepatic disease, especially lymph node metastasis, was significantly higher for patients with CK19-positive HCC. These findings indicate that CK19 expression is a predictor of early postoperative recurrence due to increased invasiveness. atients with intrahepatic cholangiocarcinoma (ICC), including combined hepatocellular and cholangiocarcinoma (cHCC-CC), exhibit poorer postoperative prognosis than those with hepatocellular carcinoma (HCC) due to more aggressive invasion and higher frequency of extrahepatic metastasis. [1][2][3][4][5][6] Thus, it is important for surgeons to take into account the presence of CC components within hepatic tumors in selecting a surgical strategy. 6) Cytokeratins (CK) are cytoskeletal intermediate filaments present in both normal and malignant epithelial cells.7) Characteristic combinations of CK polypeptides are expressed in different epithelia depending on the organ and/or type of differentiation. 7,8) In normal human liver, hepatocytes express CK8 and CK18, while bile duct cells also contain CK7 and CK19. [8][9][10][11] Since this CK pattern has been believed to be preserved during neoplastic transformation, HCC would be expected to express CK8 and CK18, but not CK7 or CK19. [8][9][10][11] Thus, expression of biliary-specific CK (CK7 and CK19) is widely used to distinguish ICC from HCC. 6,[8][9][10][11][12] Maeda et al. 6) recommended that HCC with "suggestive" CC components (incomplete gland formation without mucin production) should be categorized as cHCC-CC when "suggestive" CC components are positive for biliary markers. However, some HCCs have been reported to express biliary markers even with typical HCC growth pattern and morphologic appearance, [13][14][15][16][17] although the histogenesis of such biliary marker-positive HCC is not wellunderstood. A previous report indicated that without treatment, the prognosis is poorer for patients with biliary differentiation marker [AE1-AE3, cytokeratin (CK) 19]-positive HCC than for those without it.16) There have, however, been no studies on the clinical usefulness of biliary marker expression by HC...

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

“…The fact that some cases of hepatocellular carcinoma with ezrin expression showed negative CK19 expression may be due to the fact that cases of hepatocellular carcinoma that are consistent with a progenitor cell origin may not necessarily have positive CK19 expression, as previously described. 10 Several studies using detailed immunophenotyping, with CK19, CK7, or OV6 for example, showed that 28-50% of cases of hepatocellular carcinoma derive from progenitor cells and their progeny, 9,11,25,26 a frequency that is compatible with cases of hepatocellular carcinoma with ezrin expression. No specific marker for hepatic progenitor cell compartment has yet been described.…”

“…Several reports [8][9][10][11] have shown that patients with hepatocellular carcinomas probably derived from hepatic progenitor cells had early tumor recurrence after surgical resection or liver transplantation, suggesting that these tumors have aggressive characteristics. In this study, multivariate analysis showed that positive ezrin expression was independently associated with early recurrence after curative surgical resection in patients with hepatocellular carcinoma, as were multiple tumors.…”

“…These cases of hepatocellular carcinoma expressed progenitor cell/ductular markers such as cytokeratin (CK) 19 and/or CK7. Several studies [8][9][10][11] have also shown that hepatocellular carcinoma having immunohistochemical CK19 expression was associated with a poor prognosis and a high rate of recurrence after surgical resection. Although the mechanisms whereby such types of hepatocellular carcinoma are associated with a poor prognosis and a high rate of recurrence after surgical resection have not been elucidated, it has been reported that several genes involved in tumor invasion and metastasis are upregulated in this type of hepatocellular carcinoma, including VIL2, which encodes ezrin.…”

Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor

“…1,2 However, the survival of patients could be quite different even if they had the same tumor stage and received the same treatment, which suggests that tumor stage based on clinicopathologic findings is not sufficient to differentiate the HCC subtype. [3][4][5] Because of recent progress in identifying molecules related to characteristics of HCC and patient survival, it may be time to integrate those molecules into tumor staging systems. For example, Wu et al proposed that HCC could be classified by the presence or absence of CK19 expression, based on the evidence that HCC could originate from hepatic progenitor cells, 3,4,6 which could retain its biliary marker (cytokeratin 19 [CK19]) and progenitor cell marker (OV-6) during its differentiation into HCC.…”

“…[3][4][5] Because of recent progress in identifying molecules related to characteristics of HCC and patient survival, it may be time to integrate those molecules into tumor staging systems. For example, Wu et al proposed that HCC could be classified by the presence or absence of CK19 expression, based on the evidence that HCC could originate from hepatic progenitor cells, 3,4,6 which could retain its biliary marker (cytokeratin 19 [CK19]) and progenitor cell marker (OV-6) during its differentiation into HCC. 6 CK19 was an important structural component of the epithelial cytoskeleton, generally expressed on cholangiocytes and intrahepatic cholangiocarcinoma (ICC) cells, 7,8 and HCCs positive for CK19 were found to have ICC-like differentiation associated with poorer differentiation, higher level of cellular proliferation, and poorer survival.…”