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Review
. 2023 Apr 24;13(1):6-28.
doi: 10.1159/000530700. eCollection 2024 Feb.

Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management

Liangtao Ye  1   2 , Julia S Schneider  2 , Najib Ben Khaled  2 , Peter Schirmacher  3 , Carolin Seifert  4 , Lea Frey  4 , Yulong He  1 , Andreas Geier  5 , Enrico N De Toni  2 , Changhua Zhang  1 , Florian P Reiter  5
Affiliations
Review

Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management

Liangtao Ye et al. Liver Cancer. .

Abstract

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation.

Summary: Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies.

Key messages: In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.

Keywords: Carcinogenesis; Combined hepatocellular-cholangiocarcinoma; Diagnosis; Liver cancer; Systemic tumor therapy; Tumor biology.

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Conflict of interest statement

Florian Reiter received honoraria for lectures and travel support from the Falk Foundation, Novartis, Ipsen, Astra Zeneca, and Gilead. Najib Ben Khaled has received reimbursement for meeting attendance fees and travel expenses from EISAI and lecture honorarium from Falk. Andreas Geier is advisory board or steering committee member to AbbVie, Alexion, Bayer, BMS, EISAI, Gilead, Intercept, Ipsen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, and Sequana. Enrico De Toni has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co., Pfizer, IPSEN, and Roche; received reimbursement of meeting attendance fees and travel expenses from Arqule, AstraZeneca, BMS, Bayer, Celsion, and Roche; received lecture honoraria from BMS and Falk; and received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche. The funding agencies were not involved in the study design and the data collection, analysis, and interpretation. The other authors have no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Evolution of cHCC-iCCA classification. cHCC-iCCA, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma; ed., edition; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; WHO, World Health Organization. References: Sempoux 2019 [7], Wells 1903 [29], Allen 1949 [30], Goodman 1985 [31], Fritz 2000 [32], Bosman 2010 [33].
Fig. 2.
Fig. 2.
cHCC-iCCA classification. HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; WHO, World Health Organization (figure modified from “Treatment of Combined Hepatocellular and Cholangiocarcinoma” by Leoni 2020 [34]).
Fig. 3.
Fig. 3.
Representative images of intermediate cell carcinoma. H&E (a) and immunohistochemistry staining of intermediate cell carcinoma in a patient with CK19 (b), Arginase (c), HepPar-1 (d), Glypican-3 (e), EpCAM (f), CD34 (g), and Ladewig staining (h). Magnification, ×40, scale bar = 20 μm. H&E, hematoxylin and eosin; CK19, cytokeratin 19; HepPar-1, hepatocyte paraffin 1; EpCAM, epithelial cellular adhesion molecule.
Fig. 4.
Fig. 4.
Potential cells of origin of cHCC-iCCA under the background of the tumor microenvironment. cHCC-iCCA, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma; CLC, cholangiolocellular carcinoma; HCC, hepatocellular carcinoma; HPC, hepatic progenitor cell; iCCA, intrahepatic cholangiocarcinoma (the figure is modified based on “Cell of origin in biliary tract cancers and clinical implications” by Moeini 2021 [83]). References: Wang 2020 [89], Chen 2012 [90], Tarlow 2014 [91], Schaub 2018 [92], Hill 2018 [93].
Fig. 5.
Fig. 5.
The genetic landscape of cHCC-iCCA. Boxes show common genetic alterations in cHCC-iCCA. Some of these alterations are found in all primary liver tumors (purple box), whereas some are more common in cHCC-iCCA and HCC (blue box) or cHCC-iCCA and iCCA (orange box). Therapeutic agents approved by the FDA or EMA for a specific genetic alteration independent of tumor type are listed. cHCC-iCCA, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; n.a., not available. References: Cazals-Hatem 2004 [28], Moeini 2017 [52], Xue 2019 [61], Wang 2018 [82], Moeini 2021 [83], Coulouarn 2012 [88], Sasaki 2017 [98], Liu 2018 [101], Joseph 2019 [102], Fujimoto 2015 [103], Müller 2020 [104], Sasaki 2019 [105].
Fig. 6.
Fig. 6.
Representative images of classical type of cHCC-iCCA. a Immunohistochemistry staining of cHCC-iCCA in patient 1 by CK7 (CCA marker) and HepPar-1 (HCC marker). Magnification, ×60, scale bar = 20 μm. b H&E and immunohistochemistry staining of cHCC-iCCA in patient 2 by CK7, HepPar-1, and Arginase (HCC marker). Magnification, ×2, scale bar = 500 μm. ×5, scale bar = 200 μm. ×63, scale bar = 20 μm. CCA, cholangiocarcinoma; cHCC-iCCA, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma; CK7, cytokeratin 7; HCC, hepatocellular carcinoma; HepPar-1, hepatocyte paraffin 1; H&E, hematoxylin and eosin.
See this image and copyright information in PMC

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