Summary
Keywords
Abbreviations:
5-FU (5-Fluorouracil), AFP (alpha-fetoprotein), APHE (arterial phase hyperenhancement), CA19-9 (carbohydrate antigen 19-9), CCA (cholangiocarcinoma), CEUS (contrast-enhanced ultrasound), cHCC-CCA (combined hepatocholangiocarcinoma), CK (cytokeratin), CLC (cholangiolocellular carcinoma), EpCAM (epithelial cell adhesion molecule), FISH (fluorescence in situ hybridisation), FLC (fibrolamellar carcinoma), HAS (hepatic angiosarcoma), HCC (hepatocellular carcinoma), HEH (hepatic epithelioid haemangioendothelioma), HepPar1 (hepatocyte specific antigen antibody), iCCA (intrahepatic cholangiocarcinoma), IHC (immunohistochemistry), LI-RADS (liver imaging reporting and data system), LT (liver transplantation), RT-PCR (reverse transcription PCR), SIRT (selective internal radiation therapy), TACE (transarterial chemoembolisation), WHO (World Health Organization)- •Recent consensus has reclassified pure cholangiolocarcinoma in CCA whereas cHCC-CCA are characterised histologically by the presence of 2 distinct morphological patterns in the same lesion.
- •A unique genetic alteration drives the pathogenesis of fibrolamellar carcinoma (DNAJB1-PRKCA fusion) and hepatic haemangioendothelioma (CAMTA1-WWTR1 fusion).
- •The combination of imaging and histology, mainly using tumour and non-tumour biopsy, are required for the diagnosis of rare PLCs.
- •When feasible, liver resection is the main treatment for rare PLCs.
- •No systemic or locoregional therapies are currently validated for the treatment of any unresectable rare PLC.
- •Liver transplantation is validated for hepatic epithelioid haemangioendothelioma even in a metastatic setting, whereas this is still an area of research for small cHCC-CCA.
Background
Combined hepatocholangiocarcinoma
A matter of definition
- 1.Tumours with hepatocytic and cholangiocytic histology, mixed with a transition or separated areas within the same tumour, which can be considered cHCC-CCA.
- 2.PLCs completely composed of “intermediate cells” (intermediate cell carcinoma) – small cells of intermediate size (between that of stem cells and hepatocytes) with transitional morphology between hepatocytes and cholangiocytes. Whether these cells can be considered a subtype of cHCC-CCA is still a matter of discussion.[5],[6]
- 3.PLCs composed of pure CLC; if the main component of PLC is >80% CLC, they can be reclassified as small duct iCCAs.[6]
Epidemiology and risk factors

Author | Country | Numbers of patients | Advanced fibrosis | HCV | HBV | Alcohol | Metabolic syndrome |
---|---|---|---|---|---|---|---|
Sasaki et al. 2017 [27] | Japan | 53 | 14/24 (58%) | 9/19 (47%) | 9/44 (21%) | 2/19 (11%) | 3/19 (16%) |
Zhou et al. 2017 [153] | China | 144 | 91/144 (63.2%) | – | 101/144 (70%) | 29/144 (20%) | – |
Xue et al. 2019 [29] | China | 121 | 54/115 (47%) | 2/115 (2%) | 89/115 (77%) | – | – |
Okumura et al. 2020 [154]
Activation of the Akt/mammalian target of rapamycin pathway in combined hepatocellular carcinoma and cholangiocarcinoma: significant correlation between p-4E-BP1 expression in cholangiocarcinoma component and prognosis. Virchows Arch. 2020; 476: 881-890 | Japan | 89 | 30/89 (34%) | 29/89 (33%) | 37/89 (43%) | – | – |
Gentile et al. 2019 [19] | Systematic Review | 437 | 226/437 (52%) | 39/437 (9%) | 264/437 (60%) | – | – |
Wells et al. 2015 [22] | USA | 39 | 12/39 (31%) | 9/39 (23%) | 0/39 | 3/39(8%) | 2/39 (5%) |
Gigante et al. 2019 [23] | France | 20 | 10/20 (50%) | 1/20 (4%) | 3/20 (15%) | 8/20 (40%) | 6/20 (30%) |
De Martin 2020 [55] | France | 31 | 31/31 (100%) | – | – | 40/75 (53%) | – |
Holzner 2020 [54] | USA | 47 | 20/47 (43%) | 15/47 (32%) | 22/47 (47%) | – | – |
Genetic landscape of cHCC-CCA
Study | Classification | Type of analysis | N patients Subtypes | Fibrosis (F3-F4) | Somatic genetic alterations |
---|---|---|---|---|---|
Hepatocholangiocarcinoma | |||||
Cazals-Hatem et al. 2004 [155] | Lisa et Allen 1949 | Target sanger sequencing | 14 mixed, 1 fibrolamellar HCC 3 collision tumours | 3/15 | TP53 |
Fujimoto et al. 2015 [24] | WHO 2010 | WGS and RNA-seq | 30 Liver cancer with biliary phenotype 7cHCC-CCA +2CLC | 4/9 | TERT promoter 53%, PBMR1 20%, ARID2 27% |
Sasaki et al. 2017 [27] | WHO 2010 | Target sanger sequencing + IHC | 53 mixed tumours 4 CT, 4 TS, 20 INT, 25 CLC | 38/53 | cHCC-CCA: TERT 50%, TP53 25%, KRAS 50% ARID1A 0% Intermediate: TERT 42%, TP53 58%, , KRAS 5%, ARID1A 11% |
Moeini et al. 2017 [28] | WHO 2010 | Microarray, DNA copy number, WES | 18 mixed tumours 6 CLC/8SC/4CT | 10/18 | CLC: TP53 and IDH1 cHCC-CCA: TP53, TERT promoter, BRAF, FGFR2-BICC1 fusion |
Liu et al. 2018 [25] | WHO 2010 | WGS, WES and RNA-seq | 4 cHCC-CCA not specified | n.a. | TP53, CTNNB1 and ARID1A |
Wang et al. 2018 [31] | WHO 2010 | WES | 7 cHCC-CCA | n.a. | TP53 and ARID2 |
Xue et al. 2019 [29] | Lisa et Allen 1949 | WES, WGS, RNA-seq, | 121 tumours: 6 separate type, 56 combined type, 59 mixed type. | 54/115 | TP53 49% , TERT promoter 23%, AXIN 10%, KMT2D 9%, KEAP1 8%, ARID1A 8%, RB1 8%, CTNNB1 6%, IDH1 5% |
Joseph et al. 2019 [26] | Consensus 2019 | Target next-generation sequencing | 20CT | 15/18 | TP53 (80%), TERT (70%), ARID1A (15%), CTNNB1 (10%), AXIN1 (10%), KRAS (5%) |
Sasaki et al. 2019 [30] | Consensus 2019 | Target sequencing + IHC | 9 CT | 6/9 | TP53 (66%), TERT promoter (33%), KRAS (22%) |
Fibrolamellar carcinoma | |||||
Honeyman et al. 2014 [79] | n.a. | RNA-seq | 15 FLC | 0 | DNAJB1-PRKACA fusion (100%) |
Cornella et al. 2015 [80] | n.a. | FISH WES | 78 FLC | 0 | DNAJB1-PRKACA fusion (79%) BRCA2 (4.2%) |
Graham et al. 2015 [81] | n.a. | RT-PCR FISH | 26 FLC | 0 | DNAJB1-PRKACA fusion (100%) |
Graham et al. 2018 [86] | n.a. | FISH NGS | 3 FLC without DNAJB1-PRKACA fusion | 0 | PRKAR1A (100%) in patients with Carney syndrome and FLC |
Graham et al. 2018 [156] | n.a. | FISH | 104 typical FLC, 12 probable FLC and 9 unlikely FLC | 0 | 99% DNAJB1-PRKACA fusion in typical, 75% in probable and 0% in unlikely FLC |
Hepatic haemangioendothelioma | |||||
Tanas et al. 2011 [113] | n.a. | RNA-seq FISH | 47 haemangioendothelioma (hepatic and non-hepatic) | 0 | 89% WWTR1-CAMTA1 fusion |
Errani et al. 2011 [115] | n.a. | FISH | 17 haemangioendothelioma (hepatic and non-hepatic) | 0 | 100% WWTR1-CAMTA1 fusion |
Antonescu et al. 2013 [116] | n.a. | FISH | 10 haemangioendothelioma without WWTR1-CAMTA1 | 0 | 100% YAP1-TFE3 fusion (in tumours without WWTR1-CAMTA1 fusion) |
Flucke et al. 2014 [157] | n.a. | FISH RT-PCR | 35 haemangioendothelioma (hepatic and non-hepatic) | 0 | 94% WWTR1-CAMTA1 and 6% YAP1-TFE3 fusion |
Patel et al. 2015 [117] | n.a. | RT-PCR | 18 haemangioendothelioma (hepatic and non-hepatic) | 0 | 78% WWTR1-CAMTA1 and 6% YAP1-TFE3 fusion |
Diagnosis

Treatments
Liver resection
Liver transplantation
Locoregional treatments
Systemic treatments
Fibrolamellar carcinoma

Pathophysiology
- Engelholm L.H.
- Riaz A.
- Serra D.
- Dagnæs-Hansen F.
- Johansen J.V.
- Santoni-Rugiu E.
- et al.
Diagnosis
Treatment
Hepatic epithelioid haemangioendothelioma

Pathophysiology
Diagnosis
Treatment
Hepatic angiosarcoma
Thway K, Doyle LA, Fukayama M et Hornick JL. Angiosarcoma. The 2019 WHO Classification of Tumours of the Digestive System. Fifth Edition. Lyon (France) IARC. http://publication.iarc.fr//579.

Pathophysiology
Diagnosis
Thway K, Doyle LA, Fukayama M et Hornick JL. Angiosarcoma. The 2019 WHO Classification of Tumours of the Digestive System. Fifth Edition. Lyon (France) IARC. http://publication.iarc.fr//579.
Thway K, Doyle LA, Fukayama M et Hornick JL. Angiosarcoma. The 2019 WHO Classification of Tumours of the Digestive System. Fifth Edition. Lyon (France) IARC. http://publication.iarc.fr//579.
Treatment
Conclusion
Financial support
Authors' contributions
Conflicts of interests
Supplementary data
- Supplementary information.pdf
- disclosures.pdf
References
- Combined liver cell ahd bile duct carcinoma.Am J Pathol. 1949; 25: 647-655
- Primary duplex liver carcinoma.Am J Surg. 1932; 17: 237-241
- Combined hepatocellular-cholangiocarcinoma.in: Bosman F.T. Carnoiro F. Hruba R.H. Theise N.D. WHO classification of tumors of the digestive system. IARC Press, Lyon2010: 225-227
- The 2019 WHO classification of tumours of the digestive system.Histopathology. 2019; (Available from: https://doi.org/10.1111/his.13975)
- cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.Hepatology. 2018; 68: 113-126
- Combined hepatocellular-cholangiocarcinoma and undifferentiated primary liver carcinoma.in: Arends M.J. Fukuyama M. Klimstra D.S. WHO Classification of Tumours: Digestive System Tumours. 5th. IARC, Lyon2019: 260
- Clinicopathological significance of ‘subtypes with stem-cell feature’ in combined hepatocellular-cholangiocarcinoma.Liver Int. 2015; 35: 1024-1035
- Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification.Am J Surg Pathol. 2013; 37: 496-505
- Combined hepatocellular-cholangiocarcinoma: a population-level analysis of an uncommon primary liver tumor.Liver Transpl. 2014; 20: 952-959
- Combined hepatocellular cholangiocarcinoma: a population-based retrospective study.Am J Gastroenterol. 2019; 114: 1496-1501
- Report of the 20th Nationwide follow-up survey of primary liver cancer in Japan.Hepatol Res. 2020; 50: 15-46
- Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study.Cancer. 1985; 55: 124-135
- Combined hepatocellular-cholangiocarcinoma: a clinicopathological study.J Gastroenterol Hepatol. 1998; 13: 34-40
- Combined hepatocellular and cholangiocarcinoma: demographic, clinical, and prognostic factors.Cancer. 2002; 94: 2040-2046
- Comparison of combined hepatocellular and cholangiocarcinoma with hepatocellular carcinoma and intrahepatic cholangiocarcinoma.Surg Today. 2006; 36: 892-897
- Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies.Cancer. 1954; 7: 462-503
- A clinicopathological study on combined hepatocellular and cholangiocarcinoma.J Gastroenterol Hepatol. 1996; 11: 758-764
- Hepatic resection for combined hepatocellular and cholangiocarcinoma.Arch Surg. 2003; 138: 86-90
- Surgical treatment of hepatocholangiocarcinoma: a systematic review.Liver Cancer. 2020; 9: 15-27
- Risk factors for combined hepatocellular-cholangiocarcinoma: a hospital-based case-control study.World J Gastroenterol. 2014; 20: 12615-12620
- Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish Matched Cohort Multicenter Study.Ann Surg. 2014; (Available from:): 259
- Biphenotypic hepatic tumors: imaging findings and review of literature.Abdom Imaging. 2015; 40: 2293-2305
- Combining imaging and tumour biopsy improves the diagnosis of combined hepatocellular-cholangiocarcinoma.Liver Int. 2019; 39: 2386-2396
- Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.Nat Commun. 2015; 6: 6120
- Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity.Biochim Biophys Acta Mol Basis Dis. 2018; 1864: 2360-2368
- Genomic profiling of combined hepatocellular-cholangiocarcinoma reveals similar genetics to hepatocellular carcinoma.J Pathol. 2019; 248: 164-178
- Mutational landscape of combined hepatocellular carcinoma and cholangiocarcinoma, and its clinicopathological significance.Histopathology. 2017; 70: 423-434
- Mixed hepatocellular cholangiocarcinoma tumors: cholangiolocellular carcinoma is a distinct molecular entity.J Hepatol. 2017; 66: 952-961
- Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes.Cancer Cell. 2019; 35: 932-947.e8
- Cholangiolocellular carcinoma with “Ductal Plate Malformation” pattern may Be characterized by ARID1A genetic alterations.Am J Surg Pathol. 2019; 43: 352-360
- Whole-exome sequencing reveals the origin and evolution of hepato-cholangiocarcinoma.Nat Commun. 2018; 9: 894
- Disruption of Trp53 in livers of mice induces formation of carcinomas with bilineal differentiation.Gastroenterology. 2012; 142: 1229-1239.e3
- p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer.Cell. 2014; 158: 579-592
- A human combined hepatocellular and cholangiocarcinoma cell line (KMCH-2) that shows the features of hepatocellular carcinoma or cholangiocarcinoma under different growth conditions.J Hepatol. 1996; 24: 413-422
- Genetic classification of combined hepatocellular-cholangiocarcinoma.Hum Pathol. 2000; 31: 1011-1017
- Progenitor cells in diseased human liver.Semin Liver Dis. 2003; 23: 385-396
- Pathology of combined hepatocellular-cholangiocarcinoma.J Gastroenterol Hepatol. 2010; 25: 1485-1492
- Diagnostic value of serum biomarkers in combined hepatocelluar-cholangiocarcinoma.J Coll Physicians Surg Pak. 2020; 30: 263-267
- Imaging features of biphenotypic primary liver carcinoma (hepatocholangiocarcinoma) and the potential to mimic hepatocellular carcinoma: LI-RADS analysis of CT and MRI features in 61 cases.AJR Am J Roentgenol. 2016; 207: 25-31
- LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions.Hepatology. 2015; 61: 1056-1065
- Combined hepatocellular cholangiocarcinoma: LI-RADS v2017 categorisation for differential diagnosis and prognostication on gadoxetic acid-enhanced MR imaging.Eur Radiol. 2019; 29: 373-382
- Differentiating combined hepatocellular and cholangiocarcinoma from mass-forming intrahepatic cholangiocarcinoma using gadoxetic acid-enhanced MRI.J Magn Reson Imaging. 2012; 36: 881-889
- Detection of combined hepatocellular and cholangiocarcinomas on enhanced CT: comparison with histologic findings.Am J Roentgenol. 2005; 184: 1157-1162
- Combined hepatocellular and cholangiocellular carcinoma presenting with radiological characteristics of focal nodular hyperplasia.World J Gastroenterol. 2009; 15: 3940-3943
- Combined hepatocellular carcinoma-cholangiocarcinoma: report of MR appearance in eleven patients.J Magn Reson Imaging. 2012; 36: 1139-1147
- Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI.Am J Roentgenol. 2013; 201: 332-339
- Combined hepatocellular carcinoma and cholangiocarcinoma (biphenotypic) tumors: clinical characteristics, imaging features of contrast-enhanced ultrasound and computed tomography.BMC Cancer. 2016; 16: 158
- Imaging of combined hepatocellular-cholangiocarcinoma in cirrhosis and risk of false diagnosis of hepatocellular carcinoma.United European Gastroenterol J. 2019; 7: 69-77
- Oncologic resection for malignant tumors of the liver.Ann Surg. 2011; 253: 656-665
- Importance of surgical margin in the outcomes of hepatocholangiocarcinoma.World J Hepatol. 2017; 9: 635-641
- Preoperative prediction of hepatocellular carcinoma tumour grade and micro-vascular invasion by means of artificial neural network: a pilot study.J Hepatol. 2010; 6: 880-888
- Surgical management of intrahepatic cholangiocarcinoma in patients with cirrhosis: impact of lymphadenectomy on peri-operative outcomes.World J Surg. 2018; 42: 2551-2560
- Oncological resection for liver malignancies: can the laparoscopic approach provide benefits?.Ann Surg. 2020;
- Resection of mixed hepatocellular-cholangiocarcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma: a Western Center Experience.Liver Transpl. 2020; 26: 888-898
- Analysis of liver resection versus liver transplantation on outcome of small intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma in the setting of cirrhosis.Liver Transpl. 2020; 26: 785-798
- Propensity-matched analysis of patients with mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing liver transplantation.Liver Transpl. 2018; 24: 1384-1397
- Liver transplantation for cholangiocarcinoma and mixed hepatocellular-cholangiocarcinoma. Working Group Report from the ILTS Transplant Oncology Consensus Conference.Transplantation. 2020; 104: 1125-1130
- Nonresectable combined hepatocellular carcinoma and cholangiocarcinoma: analysis of the response and prognostic factors after transcatheter arterial chemoembolization.Radiology. 2010; 255: 270-277
- Postresection outcomes of combined hepatocellular carcinoma-cholangiocarcinoma, hepatocellular carcinoma and intrahepatic cholangiocarcinoma.J Gastrointest Surg. 2016; 20: 411-420
- The effectiveness of transarterial chemoembolization in recurrent hepatocellular-cholangiocarcinoma after resection.PLoS One. 2018; 13: e0198138
- Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial.JAMA Oncol. 2019; 6: 51-59
- Outcomes of Yttrium-90 radioembolization for unresectable combined biphenotypic hepatocellular-cholangiocarcinoma.J Vasc Interv Radiol. 2020; 31: 701-709
- Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390
- Cholangiocarcinoma — evolving concepts and therapeutic strategies.Nat Rev Clin Oncol. 2017; 15: 95
- Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma.Cancer Sci. 2018; 109: 2549-2557
- Gemcitabine plus platinum-based chemotherapy for first-line treatment of hepatocholangiocarcinoma: an AGEO French multicentre retrospective study.Br J Cancer. 2018; 118: 325-330
- Systemic therapy for combined hepatocellular-cholangiocarcinoma: a single-institution experience.J Natl Compr Canc Netw. 2018; 16: 1193-1199
- Fibrolamellar carcinoma: a concise review.Arch Pathol Lab Med. 2018; 142: 1141-1145
- Fibrolamellar carcinoma: recent advances and unresolved questions on the molecular mechanisms.Semin Liver Dis. 2018; 38: 51-59
- Fibrolamellar hepatocellular carcinoma: a population-based observational study.Dig Dis Sci. 2020;
- Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective.J Am Coll Surg. 2014; 218: 196-205
- Prognosis of patients with fibrolamellar hepatocellular carcinoma versus conventional hepatocellular carcinoma: a systematic review and meta-analysis.Gastrointest Cancer Res. 2014; 7: 49-54
- Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood.AMA J Dis Child. 1956; 91: 168-186
- Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features.Cancer. 1980; 46: 372-379
- Prognosis of fibrolamellar carcinoma compared to non-cirrhotic conventional hepatocellular carcinoma.J Gastrointest Surg. 2016; 20: 1725-1731
- Outcome of patients with fibrolamellar hepatocellular carcinoma.Cancer. 2006; 106: 1331-1338
- A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma.J Am Coll Surg. 2012; 215: 820-830
- Predictors of outcome in patients with fibrolamellar carcinoma: analysis of the National Cancer Database.Anticancer Res. 2020; 40: 847-855