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%).
[1]
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.[2]
,[3]
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.
[4]
In between, cHCC-CCA develop more often than iCCA in patients with advanced fibrosis and cirrhosis (in approximately 50% of cases).[5]
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.
[6]
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.[7]
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.[8]
Similarly, small- and large-duct iCCAs display specific gene alterations including IDH1/2 mutations and FGFR2 fusions, and SMAD4 and MDM2 mutations, respectively.[9]
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.
[10]
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.
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References
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- cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.Hepatol Baltim Md. 2018 Jan 23;
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- Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis.J Hepatol. 2020 Jan; 72: 95-103
- Surgical treatment of hepatocholangiocarcinoma: a systematic review.Liver Cancer. 2020 Jan; 9: 15-27
- Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.Nat Commun. 2015 Jan 30; 6: 6120
- A framework for fibrolamellar carcinoma research and clinical trials.Nat Rev Gastroenterol Hepatol. 2022 Feb 21;
- Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.J Hepatol. 2017 Oct; 67: 727-738
- Anatomical, histomorphological and molecular classification of cholangiocarcinoma.Liver Int Off J Int Assoc Study Liver. 2019 May; 39: 7-18
- BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA.J Hepatol. 2020 May; 72: 924-936
Article info
Publication history
Published online: September 02, 2022
Accepted:
May 30,
2022
Received in revised form:
May 9,
2022
Received:
March 24,
2022
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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