Intrahepatic Cholangiocarcinoma: A Malignancy of Increasing Importance Chet W Hammill, MD, Linda L Wong, MD, FACS Intrahepatic cholangiocarcinoma is a poorly understood biliary malignancy that is increasing in incidence because of risk factors that are just beginning to be elucidated. The literature on this disease is limited primarily to case series from specialized hepatobiliary centers. But there are no defining studies, and few case series involve more than 100 patients. In addition, there is some confusion as to classifi- cation and staging of this little known malignancy, render- ing the literature that much more challenging to interpret. It is primarily a disease of surgical importance, but minimal progress has been made in improving diagnosis and treat- ment. This article reviews current knowledge and recent discoveries on intrahepatic cholangiocarcinoma that sur- geons need to be aware of to effectively treat the disease. Classification Using the most basic definition, intrahepatic cholangiocar- cinoma (ICC) refers to the 10% of bile duct cancers that arise from the epithelial cells of the intrahepatic bile ducts. The other 90% of cholangiocarcinomas arise from the ep- ithelial cells of the extrahepatic bile ducts, and are referred to as extrahepatic cholangiocarcinoma (ECC), with the majority located near the bifurcation of the common he- patic duct. 1 Although this definition appears straightfor- ward, development of different definitions and systems of classification by various groups has led to confusion. His- torically, these cancers were classified as “biliary tract can- cers” if they were located in the extrahepatic bile ducts or “primary liver tumors” if they were located in the liver. Later “primary liver tumors” became known as “cholangio- carcinomas,” and more recently, “cholangiocarcinoma” has been expanded to describe all cancers arising from the ep- ithelial cells of the bile ducts regardless of the location. These cancers have been further classified based on their anatomic location into ICC and ECC. In the literature, ICC also is referred to as “peripheral,” based on its location in the liver, or “mass-forming,” based on its morphologic growth pattern. The delineation of ICC is a relatively re- cent phenomenon, with the earliest case reports and series in the 1970s and 1980s. 2,3 Because of these inconsistencies in definition and the relatively small numbers of cases re- ported by each group, there is currently no consensus on classification. Extrahepatic cholangiocarcinoma has been further sub- divided into several categories including hilar, perihilar, distal, and diffuse. 4,5 “Hilar cholangiocarcinoma,” also called a “Klatskin tumor,” is used to describe tumors that involve the bifurcation of the common hepatic duct. Many sources use “perihilar cholangiocarcinoma,” which in- cludes tumors of the common hepatic duct and its primary and secondary branches proximal to the bifurcation. But there is disagreement about the distal border for perihilar cholangiocarcinomas; some define it as the point at which the bile duct passes under first portion of the duodenum, and others define it as the point at which the cystic duct joins the common hepatic. Many textbooks and articles simply do not define “perihilar,” leaving readers to come to their own conclusions. Further confusion occurs because “hilar,” “perihilar,” and “Klatskin tumors” have all been used to refer to intrahepatic and extrahepatic cholangiocar- cinomas. As an example, the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), used by many of the data sources for recent publications on chol- angiocarcinoma, includes codes for Klatskin tumors (8162/3) as a subset of both ICC (C22.1) and ECC (C24.0). 6,7 Figure 1 illustrates the different anatomic clas- sifications that are currently used. In addition to anatomic classifications, many attempts have been made to categorize ICC based on specific mor- phology and histologic features. This has generated other descriptive terms such as nodular, massive, diffuse, sclerosing, polypoid, papillary, exophytic, and infiltrating. 8 More re- cently, the Liver Cancer Study Group of Japan proposed a classification consisting of “mass-forming,” “periductal- infiltrating,” and “intraductal-growing,” with morphology as illustrated in Figure 2. 9 The mass-forming subtype cor- responds to previous classifications of nodular and exo- phytic; periductal-infiltrating corresponds to the infiltrat- ing and sclerosing subtypes; and intraductal-growing corresponds to the previous subtypes of polypoid and papillary. Disclosure Information: The following disclosure has been reported by the author: Dr Wong is on the Advisory Board and has received an honorarium from Bayer Health Care. Received February 14, 2008; Revised April 14, 2008; Accepted April 22, 2008. From the Departments of Surgery, University of Hawaii John A Burns School of Medicine, and Hawaii Medical Center-East, Honolulu, HI. Correspondence address: Linda L Wong, MD, University of Hawaii, 2226 Liliha Street, Suite 402, Honolulu, HI 96817. 594 © 2008 by the American College of Surgeons ISSN 1072-7515/08/$34.00 Published by Elsevier Inc. doi:10.1016/j.jamcollsurg.2008.04.031