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Cardinale et al. Hepatoma Res 2018;4:20                          Hepatoma Research
               DOI: 10.20517/2394-5079.2018.46




               Review                                                                        Open Access


               Intrahepatic cholangiocarcinoma: review and update


               Vincenzo Cardinale *, Maria Consiglia Bragazzi *, Guido Carpino , Sabina Di Matteo , Diletta Overi ,
                                                                                                   4
                                                                                      3
                                                                      2
                                1
                                                       1
               Lorenzo Nevi , Eugenio Gaudio , Domenico Alvaro 3
                           3
                                          4
               1 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Rome 00198, Italy.
               2 Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, Rome
               00100, Italy.
               3 Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome 00198, Italy.
               4 Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza
               University of Rome, Rome 00198, Italy.
               *Authors contributed equally.
               Correspondence to: Prof. Domenico Alvaro, Department of Medicine and Medical Specialties, Sapienza University of Rome,
               Rome 00198, Italy. E-mail: domencio.alvaro@uniroma1.it
               How to cite this article: Cardinale V, Bragazzi MC, Carpino G, Di Matteo S, Overi D, Nevi L, Gaudio E, Alvaro D. Intrahepatic
               cholangiocarcinoma: review and update. Hepatoma Res 2018;4:20. http://dx.doi.org/10.20517/2394-5079.2018.46
               Received: 30 Apr 2018    First Decision: 21 May 2018    Revised: 1 Jun 2018    Accepted: 1 Jun 2018    Published: 19 Jun 2018

               Science Editor: Guang-Wen Cao    Copy Editor: Jun-Yao Li    Production Editor: Cai-Hong Wang


               Abstract
               Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that could develop at any level from the biliary
               tree. CCA is currently classified into intrahepatic (iCCA), perihilar and distal on the basis of its anatomical location. Of
               note, these three CCA subtypes have common features but also important inter-tumor and intra-tumor differences that
               can affect the pathogenesis and outcome. A unique feature of iCCA is that it recognizes as origin tissues, the hepatic
               parenchyma or large intrahepatic and extrahepatic bile ducts, which are furnished by two distinct stem cell niches, the
               canals of Hering and the peribiliary glands, respectively. The complexity of iCCA pathogenesis highlights the need of a
               multidisciplinary, translational and systemic approach to this malignancy. This review will focus on the advances of iCCA
               epidemiology, histo-morphology, risk factors, molecular pathogenesis, revealing the existence of multiple subsets of iCCA.

               Keywords: Cholangiocarcinoma, classifications, inflammation, cells of origin, stem cells, molecular profiling



               INTRODUCTION
               Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies emerging at any level from the biliary
               tree  [Figure 1]. CCA is classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) based on
                  [1-3]
               its anatomical location . Of note, these three CCA subtypes have common features but also important
                                   [1-3]
               inter-tumor and intra-tumor differences that can affect the pathogenesis and outcome . The complexity
                                                                                         [4-9]
                           © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
                           International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
                sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
                as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
                and indicate if changes were made.


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