Cholangiocarcinoma: A cancer in search of the right classification

Authors

  • Vincenzo Cardinale M.D.,

    1. Department of Medico-Surgical Sciences and Biotechnologies Polo Pontino, Italy
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  • Guido Carpino M.D., Ph.D.,

    1. Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome Rome, Italy
    2. Department of Health Sciences, University of Rome “Foro Italico” Rome, Italy
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  • Lola M. Reid Ph.D.,

    1. Department of Cell and Molecular Physiology Program in Molecular Biology and Biotechnology UNC School of Medicine Chapel Hill, NC
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  • Eugenio Gaudio M.D., Ph.D.,

    1. Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome Rome, Italy
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  • Domenico Alvaro M.D.

    1. Department of Medico-Surgical Sciences and Biotechnologies Polo Pontino, Italy
    2. Eleonora Lorillard Spencer-Cenci Foundation Rome Italy
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  • Potential conflict of interest: Nothing to report.

Cholangiocarcinoma: A Cancer in Search of the Right Classification

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.

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.

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