To the Editor:

In their letter,1 Nakanuma and Sato provide evidence that peribiliary glands (PBGs) contain cells implicated in the origin of intraductal papillary neoplasms of the bile duct. This fits well with the hypothesis that mucin-producing cholangiocarcinomas might arise from biliary tree stem/progenitor cells (BTSCs) located in the PBGs of large intra- and extrahepatic bile ducts.2 BTSCs are associated with mucin-producing cells within the liver and biliary tree.3 Figure 1 shows an example of a mucin-producing intrahepatic cholangiocarcinoma morphologically being the malignant counterpart of PBGs. Thus, intraductal papillary neoplasms could represent the preneoplastic lesions preceding the emergence of mucin-producing cholangiocarcinomas, supporting similarities between pancreatic and bile duct neoplasias. In response to injuries, pancreatic duct glands undergo a mucinous metaplasia that might lead to pancreatic cancer4; this could occur also in the biliary tree during pathologic processes with risk factors for cholangiocarcinoma, such as primary sclerosing cholangitis.5 An unresolved question has been which cells are the origin of cholangiocarcinomas. Stem cells are candidates, because their self-renewal and longevity facilitate the sequential accumulation of oncogenic mutations.6 Two stem-cell niches have been described within the liver: canals of Hering, containing hepatic stem cells, and intrahepatic PBGs, containing BTSCs.3, 7 The former has been involved in the pathogenesis of cholangiocarcinomas with mixed features,8 whereas the latter could be implicated in the carcinogenesis of mucin-producing cholangiocarcinomas. Mucin-producing intrahepatic cholangiocarcinoma should be considered as having a similar origin to hilar and extrahepatic cholangiocarcinomas, opening new perspectives in the classification of cholangiocarcinomas.

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Figure 1. Immunohistochemistry for epithelial cell adhesion molecule (EpCAM) counterstained with Periodic Acid Schiff (PAS). Original magnification: 20×. Comparison of normal peribiliary glands and mucin-producing intrahepatic cholangiocarcinoma. Mucin-producing intrahepatic cholangiocarcinoma is morphologically the malignant counterpart of peribiliary glands.

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  • 1
    Nakanuma Y, Sato Y. Cystic and papillary neoplasm involving peribiliary glands: a biliary counterpart of branch-type IPMN? Hepatology 2012 Jan 19. doi: 10.1002/hep.25590.
  • 2
    Cardinale V, Wang Y, Carpino G, Cui CB, Gatto M, Rossi M, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. HEPATOLOGY 2011; 54: 2159-2172.
  • 3
    Carpino G, Cardinale V, Onori P, Franchitto A, Berloco PB, Rossi M, et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat 2011. doi: 10.1111/j.1469-7580.2011.01462.x.
  • 4
    Strobel O, Rosow DE, Rakhlin EY, Lauwers GY, Trainor AG, Alsina J, et al. Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology 2010; 138: 1166-1177.
  • 5
    Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. HEPATOLOGY 2011; 54: 173-184.
  • 6
    Visvader JE. Cells of origin in cancer. Nature 2011; 469: 314-322.
  • 7
    Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G, et al. Human hepatic stem cell and maturational liver lineage biology. HEPATOLOGY 2011; 53: 1035-1045.
  • 8
    Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. HEPATOLOGY 2008; 47: 1544-1556.

Vincenzo Cardinale M.D.*, Yunfang Wang M.D., Ph.D.†, Guido Carpino Ph.D.‡, Lola M. Reid Ph.D.¶, Eugenio Gaudio M.D.** §, Domenico Alvaro M.D.* **, * Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Rome, Italy, † The Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, China, ‡ Department of Health Sciences, University of Rome “Foro Italico”, Rome, Italy, § Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy, ¶ Department of Cell and Molecular Physiology, Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC, ** Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy.