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Pathogenesis of primary liver carcinomas

  • Valérie Paradis
    Correspondence
    Corresponding author. Address: Centre de recherche sur l’inflammation, INSERM1149, Université Paris Cité, Paris, France.
    Affiliations
    Centre de recherche sur l’inflammation, INSERM1149, Université Paris Cité, Paris, France

    Pathology Department, Beaujon Hospital, APHP.Nord, Clichy, France
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  • Jessica Zucman-Rossi
    Affiliations
    Centre de recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France

    APHP, Institut du Cancer Paris CARPEM, APHP.centre, Hôpital Européen Georges Pompidou, Paris, France
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Published:September 02, 2022DOI:https://doi.org/10.1016/j.jhep.2022.05.037
      Primary liver cancer (PLC) is the third leading cause of cancer death, accounting for 830,180 deaths worldwide in 2020. PLCs are mainly composed of hepatocellular carcinoma (HCC, ∼85%) and intrahepatic cholangiocarcinoma (iCCA, ∼10%).
      • Gigante E.
      • Paradis V.
      • Ronot M.
      • Cauchy F.
      • Soubrane O.
      • Ganne-Carrié N.
      • et al.
      New insights into the pathophysiology and clinical care of rare primary liver cancers.
      HCC is PLC characterized by hepatocellular differentiation; in contrast, CCAs are biliary differentiated tumors. HCC and iCCA define a spectrum of PLCs that also include mixed tumors (combined HCC-CCA [cHCC-CCA]), which are much more uncommon (∼1%). They are defined by the presence of HCC and CCA areas in various proportions, as well as, in some cases, the presence of transitional features within the same tumor.
      • Brunt E.
      • Aishima S.
      • Clavien P.A.
      • Fowler K.
      • Goodman Z.
      • Gores G.
      • et al.
      cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.
      ,
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • Paradis V.
      • Rugge M.
      • Schirmacher P.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      HCC and iCCA are unique in terms of epidemiology and risk factors. While HCC mostly develops in males in the context of chronic liver diseases and cirrhosis, iCCA usually arise in the absence of underlying liver fibrosis. Usual risk factors for HCC include HCV and HBV infections, excessive alcohol intake, and non-alcoholic fatty liver disease. Cysts and stones are specifically associated with iCCA.
      • Clements O.
      • Eliahoo J.
      • Kim J.U.
      • Taylor-Robinson S.D.
      • Khan S.A.
      Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis.
      In between, cHCC-CCA develop more often than iCCA in patients with advanced fibrosis and cirrhosis (in approximately 50% of cases).
      • Gentile D.
      • Donadon M.
      • Lleo A.
      • Aghemo A.
      • Roncalli M.
      • di Tommaso L.
      • et al.
      Surgical treatment of hepatocholangiocarcinoma: a systematic review.
      Morphologically, in addition to the specific aspect of cell proliferation (hepatocyte vs. cholangiocyte), PLCs display some hallmark features that enable their differential recognition, including the desmoplastic fibrous stroma and perineural infiltration in iCCA, or the presence of bile plugs or steatosis and vascular invasion in HCC.
      At the molecular level, most of the genomic alterations identified in HCC are also found in cHCC-CCA and iCCA but at different frequencies. Overall, cHCC-CCAs more closely resemble HCC than iCCA.
      • Fujimoto A.
      • Furuta M.
      • Shiraishi Y.
      • Gotoh K.
      • Kawakami Y.
      • Arihiro K.
      • et al.
      Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.
      However, some genomic alterations are quasi-exclusively found in HCC (TERT promoter mutations, CTNNB1 mutations), in iCAA (FGF amplifications/fusion genes, KRAS, BRAF, and IDH1/2 mutations) and only in a few cases of cHCC-CCA.
      • Dinh T.A.
      • Utria A.F.
      • Barry K.C.
      • Ma R.
      • Abou-Alfa G.K.
      • Gordan J.D.
      • et al.
      A framework for fibrolamellar carcinoma research and clinical trials.
      Interestingly, specific molecular alterations in both HCC and iCCA are correlated with morphological subtypes. TP53 and CTNNB1 alterations are associated with macrotrabecular/massive and microtrabecular/pseudoglandular HCC, respectively, showing prognostic relevance.
      • Calderaro J.
      • Couchy G.
      • Imbeaud S.
      • Amaddeo G.
      • Letouzé E.
      • Blanc J.F.
      • et al.
      Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.
      Similarly, small- and large-duct iCCAs display specific gene alterations including IDH1/2 mutations and FGFR2 fusions, and SMAD4 and MDM2 mutations, respectively.
      • Kendall T.
      • Verheij J.
      • Gaudio E.
      • Evert M.
      • Guido M.
      • Goeppert B.
      • et al.
      Anatomical, histomorphological and molecular classification of cholangiocarcinoma.
      Usually, cHCC-CCAs show a liver progenitor cell phenotype with CK19, CD133 and CD56 expression. Also, among HCCs, a subtype of tumors show a progenitor phenotype and are less differentiated.
      Among PLCs, fibrolamellar carcinomas (FLCs) define a specific subgroup of HCC with specific clinical features: young age with occurrence between 10 to 35 years, a balanced sex ratio and no chronic liver disease. Also, prognosis is better, with 80% survival 5 years after resection.
      In addition, FLCs show a specific stage of differentiation with co-expression of hepatocellular (HEPPAR1), biliary (CK7), macrophage (CD68), and neuroectodermic markers.
      • Hirsch T.Z.
      • Negulescu A.
      • Gupta B.
      • Caruso S.
      • Noblet B.
      • Couchy G.
      • et al.
      BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA.
      Molecular features in FLC contrast with all other PLCs with the presence of the DNAJB1-PRKACA fusion gene exclusively observed in FLC, in the absence of other genes classically mutated in HCC and CCA. Interestingly, BAP1-mutated HCCs show frequent heterogeneous mixed FLC-HCC histology, illustrating the continuum between tumor subgroups and specific stage of differentiation and/or cell at the origin of the malignant transformation.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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