To the Editor:

We read with interest the article by Komuta et al.1 showing large differences in clinical-pathological features of intrahepatic cholangiocarcinomas (ICCs) arising from columnar mucin-producing cholangiocytes lining large bile ducts versus ones arising from cuboidal non mucin-producing cholangiocytes located in or near canals of Hering, comprised of human hepatic stem cells (hHpSCs) that are lineage-restricted to hepatocytes and cholangiocytes. These results are in keeping with previous studies dealing with the pathological, epidemiological, and clinical heterogeneity of cholangiocarcinomas (CCs)2, 3 and with the biological mechanisms underlying this heterogeneity.4 Indeed, Komuta et al. demonstrated that multiple cells of origin determine CC clinical-pathological differences and suggested that mixed-ICC and cholangiolocarcinoma (CLC) are completely separate entities with respect to the pure mucin-producing ICC (muc-ICC). Recently, Nakanuma and Sato5 provided evidence that peribiliary glands (PBGs) could be involved in the origin of intraductal papillary neoplasms of the bile duct, a preneoplastic lesion of muc-ICC. This confirms that human biliary tree stem cells (hBTSCs), residing in PBGs,6 are probable cells of origin of muc-ICCs. The results by Komuta et al.,1 together with advances with respect to stem cell biology,6, 7 and the relationship between tumor types and their normal stem cell counterparts,4 enable a CCs classification based on cells of origin. Hypothetically, the mixed-ICCs originate from cells from hHpSC-derived lineages,7 whereas pure mucin-producing CCs (intra- and extrahepatic) originate from hBTSC-derived lineages. Based on the grade of maturation of the cell of origin within the two lineages, CCs can be reclassified as:

  • CCs with focal hepatocytic differentiation from hHpSC-derived lineages: combined hepatocellular-cholangiocarcinoma, mixed-CC, and CCL.

  • Pure mucin-producing CCs from hBTSC-derived lineages in PBGs or from epithelium of intra- or extrahepatic large bile ducts: hilar CC and muc-ICC.

A CCs classification based on the cell-lineages-of-origin is more coherent with current knowledge on the epidemiology and risk factors and may have important clinical implications for the definition of specific therapeutic targets.


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  • 1
    Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, et al. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. HEPATOLOGY 2012;55:1876-1888.
  • 2
    Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC, et al. Intra-hepatic and extra-hepatic cholangiocarcinoma: new insight into epidemiology and risk factors. World J Gastrointest Oncol 2010; 2: 407-416.
  • 3
    Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H. Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol 2010; 2: 419-427.
  • 4
    Visvader JE. Cells of origin in cancer. Nature 2011; 469: 314-322.
  • 5
    Nakanuma Y, Sato Y. Cystic and papillary neoplasm involving peribiliary glands: a biliary counterpart of branch-type IPMN? HEPATOLOGY 2012;55:2040-2041.
  • 6
    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: 21592172.
  • 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: 10351045.

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