Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile duct adenoma (BDA), biliary adenofibroma (BAF), and von Meyenburg complexes (VMCs) are reportedly followed by development of ICCs. Herein, we surveyed these candidate precursor lesions in the background liver of 37 cases of peripheral ICC and controls (perihilar CC, 34 cases; hepatocellular carcinoma, 34 cases and combined hepatocellular cholangiocarcinoma, 25 cases). In the background liver of peripheral ICC, BDA and BAF were not found, but there were not infrequently foci of BDA-like lesions and atypical bile duct lesions involving small bile ducts (32.4% and 10.8%, resp.). VMCs were equally found in peripheral CCs and also control CCs. In conclusion, BDA, BAF, and VMCs are a possible precursor lesion of a minority of peripheral CCs, and BDA-like lesions and atypical bile duct lesions involving small bile ducts may also be related to the development of peripheral ICC. Further pathologic studies on these lesions are warranted for analysis of development of peripheral ICCs. 1. Introduction Cholangiocarcinoma (CC) is an intractable malignant tumor with a poor prognosis. Surgical resection of CC at an early stage is crucial to improve the prognosis of CC patients [1, 2]. However, this procedure is not applicable to the majority of these patients because most CCs are diagnosed or detected at an advanced stage, and treatment options remain limited [3]. CC is generally divided into distal and perihilar CCs and intrahepatic CC (ICC) [4, 5], and their clinicopathological features, risk factors, and epidemiology are different among them [2, 6, 7]. ICC is the second most common liver primary tumor after HCC, and its incidence has increased in recent years [7–9]. ICCs themselves are known to exhibit heterogeneity in their location in the liver, histopathologies, and expression of markers [8], and this heterogeneity may reflect the heterogeneous cholangiocytes along the biliary tree [4, 6, 10, 11]. ICC can be further divided into large bile duct ICC and peripheral ICC [12]. In distal, perihilar, and intrahepatic large duct, cylindrical mucin-producing cholangiocytes are located in large bile ducts, while cuboidal non-mucin-producing cholangiocytes are located in small bile ducts and bile ductules containing bipotential
References
[1]
M. Nagino, T. Ebata, Y. Yokoyama et al., “Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections,” Annals of Surgery, vol. 258, pp. 129–140, 2013.
[2]
S. Rizvi and G. J. Gores, “Pathogenesis, diagnosis, and management of cholangiocarcinoma,” Gastroenterology, vol. 145, no. 6, pp. 1215–1229, 2013.
[3]
R. Higuchi, T. Ota, T. Araida, M. Kobayashi, T. Furukawa, and M. Yamamoto, “Prognostic relevance of ductal margins in operative resection of bile duct cancer,” Surgery, vol. 148, no. 1, pp. 7–14, 2010.
[4]
Y. Nakanuma, M. P. Curabo, S. Franceschi et al., “Intrahepatic cholangiocarcinoma,” in WHO Classification of Tumours of the Digestive System; World Health Organization of Tumours, F. T. Bosman, F. Carneiro, R. H. Hruban, and N. D. Theise, Eds., pp. 217–224, IARC, Lyon, France, 4th edition, 2010.
[5]
J. Albores-Saavedra, N. V. Adsay, J. M. Crawford et al., “Carcinoma of the gallbladder and extrahepatic bile ducts,” in WHO Classification of Tumours of the Digestive System; World Health Organization of Tumours, F. T. Bosman, F. Carneiro, R. H. Hruban, and N. D. Theise, Eds., pp. 266–273, IARC, Lyon, France, 4th edition, 2010.
[6]
M. Komuta, O. Govaere, V. Vandecaveye, et al., “Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes,” Hepatology, vol. 55, pp. 1876–1888, 2012.
[7]
T. Patel, “New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma,” Journal of Gastroenterology, vol. 49, no. 2, pp. 165–172, 2014.
[8]
A. M. Xu, Z. H. Xian, S. H. Zhang, and X. F. Chen, “Intrahepatic cholangiocarcinoma arising in multiple bile duct hamartomas: report of two cases and review of the literature,” European Journal of Gastroenterology and Hepatology, vol. 21, pp. 580–584, 2009.
[9]
Y. Shaib and H. B. El-Serag, “The epidemiology of cholangiocarcinoma,” Seminars in Liver Disease, vol. 24, pp. 115–125, 2004.
[10]
K. Harada, Y. Nakanuma, and H. Ikeda, “Heterogeneity in intrahepatic cholangiocarcinoma,” Hepatology Research, 2014, in press.
[11]
C. Gandou, K. Harada, Y. Sato, et al., “Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies, immunophenotypes, and development-related molecules,” Human Pathology, vol. 44, pp. 811–821, 2013.
[12]
Y. Nakanuma, Y. Sato, K. Harada, M. Sasaki, J. Xu, and H. Ikeda, “Pathological classification of intrahepatic cholangiocarcinoma based on a new concept,” World Journal of Hepatology, vol. 2, pp. 419–427, 2010.
[13]
M. Komuta, B. Spee, S. V. Borght et al., “Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin,” Hepatology, vol. 47, no. 5, pp. 1544–1556, 2008.
[14]
C. Sempoux, C. Fan, P. Singh et al., “Cholangiolocellular carcinoma: an innocent-looking malignant liver tumor mimicking ductular reaction,” Seminars in Liver Disease, vol. 31, no. 1, pp. 104–110, 2011.
[15]
Y. Zen, M. Sasaki, T. Fujii et al., “Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct—an immunohistochemical study of 110 cases of hepatolithiasis,” Journal of Hepatology, vol. 44, no. 2, pp. 350–358, 2006.
[16]
Y. Jiao, T. M. Pawlik, R. A. Anders, et al., “Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas,” Nature Genetics, 2013.
[17]
O. Akin and M. Coskun, “Biliary adenofibroma with malignant transformation and pulmonary metastases: CT findings,” American Journal of Roentgenology, vol. 179, no. 1, pp. 280–281, 2002.
[18]
G. S. Allaire, L. Rabin, K. G. Ishak, and I. A. Sesterhenn, “Bile duct adenoma. A study of 152 cases,” American Journal of Surgical Pathology, vol. 12, no. 9, pp. 708–715, 1988.
[19]
Y. Nakanuma, Y. Sato, H. Ikeda, et al., “Intrahepatic cholangiocarcinoma with predominant “ductal plate malformation” pattern: a new subtype,” American Journal of Surgical Pathology, vol. 36, pp. 1629–1635, 2012.
[20]
K. Kozaka, M. Sasaki, T. Fujii et al., “A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: “Bile ductular carcinoma”,” Histopathology, vol. 51, no. 3, pp. 390–400, 2007.
[21]
Y. Nakanuma, M. Hoso, T. Sanzen, and M. Sasaki, “Microstructure and development of the normal and pathologic biliary tract in humans, including blood supply,” Microscopy Research and Technique, vol. 38, pp. 552–570, 1997.
[22]
A. C. Pinho, R. B. Melo, M. Oliveira et al., “Adenoma-carcinoma sequence in intrahepatic cholangiocarcinoma,” International Journal of Surgery Case Reports, vol. 3, pp. 131–133, 2012.
[23]
K. G. Ishak, Z. D. Goodman, and J. T. Stocker, “Benign cholangiocellular tumors,” in Tumors of the Liver and Intrahepatic Bile Ducts, J. Rosai and L.H. Sobin, Eds., Tumor Pathology 3rd series, pp. 49–70, Armed Force Institute of Pathology (AFIP), Washington, DC, USA, 2001.
[24]
W. M. S. Tsui, K. T. Loo, L. T. C. Chow, and C. C. H. Tse, “Biliary adenofibroma: a heretofore unrecognized benign biliary tumor of the liver,” American Journal of Surgical Pathology, vol. 17, no. 2, pp. 186–192, 1993.
[25]
P. J. Karhunen, “Adult polycystic liver disease and biliary microhamartomas (von Meyenburg's complexes),” Acta Pathologica Microbiologica et Immunologica Scandinavica, vol. 94, no. 6, pp. 397–400, 1986.
[26]
M. S. Redston and I. R. Wanless, “The hepatic von Meyenburg complex with hepatic and renal cysts,” Modern Pathology, vol. 9, no. 3, pp. 233–237, 1996.
[27]
J. S. Song, Y. J. Lee, K. W. Kim, J. Huh, S. J. Jang, and E. Yu, “Cholangiocarcinoma arising in von Meyenburg complexes: report of four cases,” Pathology International, vol. 58, pp. 503–512, 2008.
[28]
D. Jain, V. R. Sarode, F. W. Abdul-Karim, R. Homer, and M. E. Robert, “Evidence for the neoplastic transformation of von-Meyenburg complexes,” American Journal of Surgical Pathology, vol. 24, pp. 1131–1139, 2000.
[29]
T. Orii, N. Ohkohchi, K. Sasaki, S. Satomi, M. Watanabe, and T. Moriya, “Cholangiocarcinoma arising from preexisting biliary hamartoma of liver—report of a case,” Hepato-Gastroenterology, vol. 50, no. 50, pp. 333–336, 2003.
[30]
M. R. O'Dell, J. L. Huang, C. L. Whitney-Miller et al., “KrasG12D and p53 mutation cause primary intrahepatic cholangiocarcinoma,” Cancer Research, vol. 72, no. 6, pp. 1557–1567, 2012.
[31]
Y. Nakanuma, T. Terada, G. Ohta, M. Kurachi, and F. Matsubara, “Caroli's disease in congenital hepatic fibrosis and infantile polycystic disease,” Liver, vol. 2, pp. 346–354, 1982.
[32]
T. Sanzen, K. Harada, M. Yasoshima, Y. Kawamura, M. Ishibashi, and Y. Nakanuma, “Polycystic kidney rat is a novel animal model of Caroli's disease associated with congenital hepatic fibrosis,” American Journal of Pathology, vol. 158, no. 5, pp. 1605–1612, 2001.
