Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin-producing cholangiocytes are located in large bile ducts and the cuboidal non–mucin-producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so-called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC-1, KMCH-1, and KMCH-2. Among 51 ICCs, 31 (60.8%) contained only mucin-producing CC features (muc-ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed-ICCs). Clinicopathologically, muc-ICCs and hilar CCs showed a predominantly (peri-)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed-ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc-ICCs and hilar CCs and in mixed-ICCs and CLCs. S100P and MUC1 were significantly up-regulated in hilar CCs and muc-ICCs compared with mixed-ICCs and CLCs, whereas NCAM1 and ALB tended to be up-regulated in mixed-ICCs and CLCs compared with other tumors. KMC-1 showed significantly higher invasiveness than KMCH-1 and KMCH-2. Conclusion: Muc-ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin-producing cholangiocytes), whereas mixed-ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin.
PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3 based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4 and NFS. This article is protected by copyright. All rights reserved.
We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi‐institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small‐sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa‐fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06‐2.19], P = 0.023), disease‐free survival (HR: 1.66 [1.21‐2.27], P = 0.002), and overall survival (HR: 2.26 [1.37‐3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β‐catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.
Interferon alfa (IFN-␣) has been shown to possess antiviral activity, antiproliferative activity, and various immunoregulatory activities including: 1) stimulation of cytotoxic activities of lymphocytes and macrophages, and of natural killer cell activity; and 2) induction of class I major histocompatibility complex antigens. 1 The effects of IFN-␣ are mediated through interaction with the specific cell-surface receptor, type I IFN receptor. This receptor consists of two chains, Hu-IFN-␣R1 and Hu-IFN-␣R2, which can be present in different forms. [2][3][4][5][6] The Hu-IFN-␣R1 chain is present as either the full chain (Hu-IFN-␣R1) or a splice-variant (Hu-IFN-␣R1s) lacking exons 4 and 5. Hu-IFN-␣R2 chain exists in soluble, short, and long forms (Hu-IFN-␣R2a, Hu-IFN-␣R2b, and Hu-IFN␣R2c, respectively). [2][3][4] Most likely, the Hu-IFN-␣R1 and Hu-IFN-␣R2c chains represent the predominantly active form. 2 Binding of the receptor and IFN-␣ induce transcription of IFN-inducible genes through the activation of the Jak/signal transducer and activator of transcription (STAT) signaling pathway. 7-9 Interferon regulatory factor (IRF)-1, a transcriptional activator, and its antagonistic repressor, IRF-2, have been identified as regulators of type I IFN (mainly IFN-␣ and IFN-) and IFN-inducible genes. 10-12 IRF-1 has recently been shown to inhibit cell proliferation, induce apoptosis, and manifest antioncogenic activities, 10,13-17 while IRF-2 has the oncogenic potential. 10 The IRF-1 gene itself is IFN-inducible and may thus be one of the critical target genes mediating IFN action. 11 Antivirus activity of IFN-␣ has attracted a great deal of attention, and IFN-␣ has been applied in treatment for hepatitis B virus (HBV)-and hepatitis C virus (HCV)-related chronic hepatitis in several countries (reviewed in Gutterman 18 ). In the liver of HCV-infected patients, expressions of Hu-IFN-␣R1 and Hu-IFN-␣R2 chains were investigated in terms of mRNA level, and the relationship between their expression levels and response to IFN-␣ therapy was reported. 19,20 Although IFN-␣ has been proven to have a curative potential in treatment of HBV-and HCV-associated chronic liver diseases, its effect on hepatocellular carcinoma (HCC), which is a common and often fatal complication of HBV-and HCV-related chronic liver diseases, 21 is not well known. Clinical trials of IFN-␣ in treatment of HCC did not achieve consistent results: one study showed beneficial effects, 22 and the other studies did not show significant antitumor effects. 23,24 In contrast, IFN-␣ has been shown to be useful for the treatment of several malignant diseases, including hairy-cell leukemia and chronic myelogenous leukemia (reviewed in Gutterman 18 ).Experimental studies showed that IFN-␣ can inhibit the growth of various normal and malignant cells in vitro by inducing cell-cycle changes (e.g., induction of G 0 /G 1 arrest and prolongation of the S phase) 25-34 and/or apoptoAbbreviations: IFN-␣, interferon alfa; STAT, signal transducer and activator of transcription; IRF, ...
Combined hepatocellular-cholangiocarcinoma comprises <1% of all liver carcinomas. The histogenesis of combined hepatocellular-cholangiocarcinoma has remained unclear for many years. However, recent advances in hepatic progenitor cell (HPC) investigations have provided new insights. The concept that combined hepatocellular-cholangiocarcinoma originates from HPCs is adopted in the chapter "combined hepatocellular-cholangiocarcinoma" of the latest World Health Organization (WHO) classification. In this study, we conducted clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification. Fifty-four cases were included in this study. Pathologic diagnosis was made according to the WHO classification. When a tumor contained plural histologic patterns, predominant histologic pattern (≥50%) was defined. Minor histologic patterns were also appended. Immunohistochemical staining with biliary markers (CK7, CK19, and EMA), hepatocyte paraffin (HepPar)-1, HPC markers (CD56, c-kit, CD133, and EpCAM), and vimentin was performed. Forty-five and 50 patients were analyzed for progression-free survival and overall survival, respectively. Ten, 1, 32, and 11 cases were diagnosed as: combined hepatocellular-cholangiocarcinoma, classical type; combined hepatocellular-cholangiocarcinoma, stem cell features, typical subtype; combined hepatocellular-cholangiocarcinoma, stem cell features, intermediate cell subtype; and combined hepatocellular-cholangiocarcinoma, stem cell features, cholangiolocellular type, respectively. Combined hepatocellular-cholangiocarcinomas usually have high expression of biliary markers. CD56, c-kit, and EpCAM were expressed to various degrees in all combined hepatocellular-cholangiocarcinomas apart from the hepatocellular carcinoma component of combined hepatocellular-cholangiocarcinoma, classical type. The expression of CD133 and vimentin was observed only in combined hepatocellular-cholangiocarcinoma, stem cell features of intermediate cell subtype and cholangiolocellular subtype. The expression of CD133, EpCAM, and vimentin was significantly high in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, especially cholangiolocellular subtype. Minor histologic patterns were significantly frequent in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, compared with combined hepatocellular-cholangiocarcinoma, classical type. There was no significant difference in clinical outcome between each subtype. Combined hepatocellular-cholangiocarcinoma has wide histologic diversity and shows immunophenotypic expression of not only biliary markers but also HPC markers to various degrees, suggesting that the histogenesis of combined hepatocellular-cholangiocarcinoma could be strongly associated with HPCs. Our results pathologically validate the latest WHO classification of combined hepatocellular-cholangiocarcinoma. However, the complex mixture of histologic subtypes has presented a challenge to the classification of combined ...
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