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      Clinical features, histology, and histogenesis of combined hepatocellular-cholangiocarcinoma


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          Combined hepatocellular-cholangiocarcinoma (CHC) is a rare tumor with poor prognosis, with incidence ranging from 1.0%-4.7% of all primary hepatic tumors. This entity will be soon renamed as hepato-cholangiocarcinoma. The known risk factors for hepatocellular carcinoma (HCC) have been implicated for CHC including viral hepatitis and cirrhosis. It is difficult to diagnose this tumor pre-operatively. The predominant histologic component within the tumor largely determines the predominant radiographic features making it a difficult distinction. Heterogeneous and overlapping imaging features of HCC and cholangiocarcinoma should raise the suspicion for CHC and multiple core biopsies (from different areas of tumor) are recommended before administering treatment. Serum tumor markers CA19-9 and alpha-fetoprotein can aid in the diagnosis, but it remains a challenging diagnosis prior to resection. There is sufficient data to support bipotent hepatic progenitor cells as the cell of origin for CHC. The current World Health Organization classification categorizes two main types of CHC based on histo-morphological features: Classical type and CHC with stem cell features. Liver transplant is one of the available treatment modalities with other management options including transarterial chemoembolization, radiofrequency ablation, and percutaneous ethanol injection. We present a review paper on CHC highlighting the risk factors, origin, histological classification and therapeutic modalities.

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          Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.

          Cholangiolocellular carcinoma (CLC), a subtype of cholangiocellular carcinoma (CC), is thought to originate from the ductules/canals of Hering, where hepatic progenitor cells (HPCs) are located. We investigated the clinicopathological features of 30 CLCs and their relationship to HPCs. We evaluated the expression of hepatocytic markers (hepatocyte paraffin-1, canalicular polyclonal carcinoembryonic antigen, and CD10), biliary/HPC markers (keratin [K]7, K19, and neural cell adhesion molecule), the adenosine triphosphate binding cassette transporters: multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1, MRP3, and breast cancer resistance protein, using immunohistochemistry and electron microscopy. In addition, gene expression profiling of CLC was performed and compared with the profile of hepatocellular carcinoma (HCC) with or without HPC features (K19 expression). In surrounding nontumoral tissue, K7-positive and K19-positive HPCs/ductular reaction were observed. More than 90% of the tumor was composed of CLC areas that showed small monotonous and/or anastomosing glands, strongly positive for K7 and K19. Especially at the tumor boundary, all cases showed a HCC-like trabecular area characterized by canalicular CD10/polyclonal carcinoembryonic antigen expression, and submembranous K7 expression, similar to intermediate hepatocytes. K7-positive/K19-positive HPCs were also seen. Out of 30 cases, 19 showed papillary and/or clear glandular formation with mucin production, representing CC areas. These three different areas showed transitional zones with each other. We observed an increased expression of MRP1, MRP3, and breast cancer resistance protein in the tumor. Electron microscopy findings in HCC-like trabecular areas confirmed the presence of HPCs and intermediate hepatocytes. HPC markers, K7, K19, prominin-1, receptor for stem cell factor c-kit, octamer-4 transcription factor, and leukemia inhibitory factor were upregulated (P < 0.05), while albumin was downregulated in CLC (P = 0.007) toward K19-negative HCCs. Comparison of CLC with K19-positive HCCs indicated a high homology. All these findings highly suggest a progenitor cell origin of CLC.
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            Combined liver cell and bile duct carcinoma.

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              Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.

              Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.

                Author and article information

                World J Hepatol
                World Journal of Hepatology
                Baishideng Publishing Group Inc
                28 February 2017
                28 February 2017
                : 9
                : 6
                : 300-309
                Shweta Gera, Department of Pathology, Montefiore Medical Center, Bronx, NY 10467, United States
                Shweta Gera, Mark Ettel, Gabriel Acosta-Gonzalez, Ruliang Xu, Department of Pathology, NYU Langone Medical Center, New York, NY 10016, United States
                Author notes

                Author contributions: Gera S contributed to writing introduction, histogenesis and histology section, drafting, designing and revision of the manuscript; Ettel M contributed to writing clinical features, histogenesis, designing and revision of the manuscript; Acosta-Gonzalez G contributed to writing clinical features, imaging and management section and revision of the manuscript; Xu R contributed to supervision, drafting, designing and revision of the manuscript.

                Correspondence to: Ruliang Xu, MD, PhD, Department of Pathology, NYU Langone Medical Center, 560 First Avenue, New York, NY 10016, United States. ruliang.xu@ 123456nyumc.org

                Telephone: +1-212-2630728 Fax: +1-212-2637916

                ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.


                combined hepatocellular-cholangiocellular carcinoma,hepatocellular carcinoma,cholangiocellular carcinoma,hepatic progenitor cell(s),histogenesis,classification


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