Cholangiocarcinoma News

Combined Hepatocellular Cholangiocarcinoma

June 2023, Vol 4, No 2
Jennifer J Knox, MD, MSc, FRCPC
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre; Department of Oncology, University of Toronto, Toronto, Ontario, Canada
Gordon T Moffat, MD, FRCPC
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre; Department of Oncology, University of Toronto, Toronto, Ontario, Canada

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a unique malignancy comprised of both hepatocellular carcinoma (HCC) from hepatocytes and cholangiocarcinoma (CCA) from bile duct epithelial cells within the same tumor.1 Initially thought to be a rare entity, the incidence is increasing (up to 14%), yet recognition remains low.2-5 Risk factors for cHCC-CCA are similar in both diseases, and include hepatitis B and C, nonalcoholic fatty liver disease, and cirrhosis.2 The pathogenesis is not entirely known but involves bipotent hepatic progenitor cells capable of undergoing bidirectional differentiation into hepatocytes and bile duct epithelial cells based on the various growth conditions.6

The clinical presentation of cHCC-CCA is similar in both diseases and includes many nonspecific symptoms. In addition, the tumor can have radiographic elements of both HCC and CCA and would be missed without pathology. Investigators found that characteristic features of cHCC-CCA include satellite nodules, a hyperintense signal on T2-weighted images, restricted diffusion, and the absence of capsule appearance on magnetic resonance imaging.7 Regarding tumor markers, only 15% of patients with cHCC-CCA will have an elevation of both alpha-fetoprotein (AFP) and carbohydrate antigen 19-9, whereas the majority of patients will have an elevated AFP alone.8 Compared with HCC, patients with cHCC-CCA tend to have lower levels of elevated AFP.6 Therefore, with all these confounding factors, the diagnosis must be based on a biopsy or surgical pathological findings.

Histologically, cHCC-CCA contains areas of both typical HCC and intrahepatic CCA (iCCA) in separate, intermixed, or focal arrangements. The diagnosis relies on routine histochemical stains with immunohistochemistry used as a supplemental diagnostic tool.9 Unequivocal histological components of both HCC and iCCA must be present to diagnose cHCC-CCA.10 Each tumor has a unique arrangement and proportion of each histology, resulting in a heterogenous group of malignancies with complex phenotypes leading to diagnostic, prognostic, and therapeutic challenges.11,12 Genomic studies have shown that cHCC-CCA is genetically distinct from HCC and CCA.13 Common genomic alterations (GAs) in cHCC-CCA include TERT, TP53, PTEN, CCND1, and CDKN2A.10,13,14 In a study by Murugesan and colleagues, 24.6% of patients with cHCC-CCA harbored a potentially actionable GA, including BRCA2, ERRB2, MET, FGFR2, and IDH1,14 which are also targets that should not be missed in CCA.

Liver transplantation and surgical resection are the only curative treatments for cHCC-CCA and should remain the first choice of treatment, if possible.15 However, fewer than half of the patients with localized disease receive cytoreductive surgery.12 In addition, the recurrence rate is 40%, and the average 5-year survival is only 30%.6,16 In a meta-analysis of 1691 patients comparing those who underwent a liver resection versus those who received transplantation, no significant differences were seen in the tumor recurrence rate or overall survival (OS) between the 2 interventions.17 If amenable, transarterial chemoembolization (TACE) has been shown to produce an improved survival benefit and may downstage cHCC-CCA for surgical treatments.2,18 Patient survival after TACE for cHCC-CCA is significantly dependent on tumor size and vascularity, Child-Pugh class, and the presence of portal vein invasion.19

The role of systemic therapy in the management of cHCC-CCA remains unclear, and current practices are based on published case reports, case series, and small retrospective studies.15 Currently, there is no standard treatment established, and strategies are taken from the management of HCC and CCA.15 In a retrospective study by Kobayashi and colleagues in 36 patients, the median OS (mOS) was 11.9, 10.2, and 3.5 months in patients with advanced cHCC-CCA treated with gemcitabine/cisplatin, gemcitabine and 5-FU, or sorafenib, respectively20; however, these outcomes were likely biased by patient selection. In a larger retrospective study by Trikalinos and colleagues in 68 patients, similar results were seen favoring chemotherapy over sorafenib.21 However, in a 2023 retrospective multicenter study (n=44), the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and OS were similar between patients who received cytotoxic chemotherapy and those who received noncytotoxic chemotherapy (sorafenib) in the multivariable analysis.22 Furthermore, based on evidence from the IMbrave-150 trial for HCC and the TOPAZ-1 trial for biliary tract cancer, there is a role for exploring immunotherapy in the management of cHCC-CCA.22 In a retrospective study by Pomej and colleagues, 7 patients with cHCC-CCA treated with an immune checkpoint inhibitor experienced an ORR of 29%, DCR of 43%, PFS of 4.1 months, and mOS of 18 months.22 Therefore, the debate for the optimal line of systemic therapy for cHCC-CCA is ongoing and evolving.

Overall, cHCC-CCA is an aggressive malignancy with histological and biological heterogeneity, treatment ambiguity, and decreased survival outcomes compared with HCC or CCA.6 Clinicians must become aware of the cHCC-CCA subtype and its diagnostic, prognostic, and therapeutic challenges. The diagnosis of cHCC-CCA should be considered in patients with radiographic features of either HCC or CCA and discordant or dual elevated tumor markers.6,23 Consideration of biopsy in all patients well enough for treatment is necessary for an accurate diagnosis; consideration of genomic sequencing and molecular profiling is necessary to potentially identify any targetable driver mutations. Approximately 25% of patients with cHCC-CCA harbor a potentially actionable alteration that could translate into more treatment options with precision choices.14 Because most patients with cHCC-CCA will require systemic therapy, there is a need to establish a standard-of-care therapy. Traditionally, patients with cHCC-CCA have been excluded from clinical trials; however, this patient population requires prospective treatment data and inclusion in future clinical research. Until then, more real-world data and larger retrospective studies are requisite to add to the paucity of information and growing discussion on management.


  1. Goodman ZD, Ishak KG, Langloss JM, et al. Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study. Cancer. 1985;55:124-135.
  2. Chen P-D, Chen L-J, Chang Y-J, et al. Long-term survival of combined hepatocellular-cholangiocarcinoma: a nationwide study. Oncologist. 2021;26(10):e1774-e1785.
  3. Jarnagin WR, Weber S, Tickoo SK, et al. Combined hepatocellular and cholangiocarcinoma. Cancer. 2002;94:2040-2046.
  4. Koh KC, Lee H, Choi MS, et al. Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg. 2005;189:120-125.
  5. Lee CC, Wu CY, Chen JT, et al. Comparing combined hepatocellular-cholangiocarcinoma and cholangiocarcinoma: a clinicopathological study. Hepatogastroenterology. 2002;49:1487-1490.
  6. Stavraka C, Rush H, Ross P. Combined hepatocellular cholangiocarcinoma (cHCC-CC): an update of genetics, molecular biology, and therapeutic interventions. J Hepatocell Carcinoma. 2018;6:11-21.
  7. Granata V, Fusco R, Venanzio Setola S, et al. Major and ancillary features according to LI-RADS in the assessment of combined hepatocellular-cholangiocarcinoma. Radiol Oncol. 2020;54:149-158.
  8. Li R, Yang D, Tang CL, et al. Combined hepatocellular carcinoma and cholangiocarcinoma (biphenotypic) tumors: clinical characteristics, imaging features of contrast-enhanced ultrasound and computed tomography. BMC Cancer. 2016;16:158.
  9. Brunt E, Aishima S, Clavien PA, et al. cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation. Hepatology. 2018;68:113-126.
  10. Choi JH, Ro JY. Combined hepatocellular-cholangiocarcinoma: an update on pathology and diagnostic approach. Biomedicines. 2022;10(8):1826.
  11. Komuta M, Yeh MM. A review on the update of combined hepatocellular cholangiocarcinoma. Semin Liver Dis. 2020;40:124-130.
  12. Wang J, Wang F, Kessinger A. Outcome of combined hepatocellular and cholangiocarcinoma of the liver. J Oncol. 2010;2010:917356.
  13. Azizi AA, Hadjinicolaou AV, Goncalves C, et al. Update on the genetics of and systemic therapy options for combined hepatocellular cholangiocarcinoma. Front Oncol. 2020;10:570958.
  14. Murugesan K, Sharaf R, Montesion M, et al. Genomic profiling of combined hepatocellular cholangiocarcinoma reveals genomics similar to either hepatocellular carcinoma or cholangiocarcinoma. JCO Precis Oncol. 2021;5:PO.20.00397.
  15. Leoni S, Sansone V, Lorenzo SD, et al. Treatment of combined hepatocellular and cholangiocarcinoma. Cancers (Basel). 2020;12(4):794.
  16. Cutolo C, Dell'Aversana F, Fusco R, et al. Combined hepatocellular-cholangiocarcinoma: what the multidisciplinary team should know. Diagnostics (Basel). 2022;12(4):890.
  17. Li DB, Si XY, Wang SJ, et al. Long-term outcomes of combined hepatocellular-cholangiocarcinoma after hepatectomy or liver transplantation: a systematic review and meta-analysis. Hepatobiliary Pancreat Dis Int. 2019;18(1):12-18.
  18. Fowler K, Saad NE, Brunt E, et al. Biphenotypic primary liver carcinomas: assessing outcomes of hepatic directed therapy. Ann Surg Oncol. 2015;22:4130-4137.
  19. Kim JH, Yoon H-K, Ko G-Y, et al. Nonresectable combined hepatocellular carcinoma and cholangiocarcinoma: analysis of the response and prognostic factors after transcatheter arterial chemoembolization. Radiology. 2010;255(1):270-277.
  20. Kobayashi S, Terashima T, Shiba S, et al. Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. Cancer Sci. 2018;109(8):2549-2557.
  21. Trikalinos NA, Zhou A, Doyle MBM, et al. Systemic therapy for combined hepatocellular-cholangiocarcinoma: a single-institution experience. J Natl Compr Canc Netw. 2018;16(10):1193-1199.
  22. Pomej K, Balcar L, Shmanko K, et al. Clinical characteristics and outcome of patients with combined hepatocellular-cholangiocarcinoma—a European multicenter cohort. ESMO Open. 2023;8:100783.
  23. Wells ML, Venkatesh SK, Chandan VS, et al. Biphenotypic hepatic tumors: imaging findings and review of literature. Abdom Imaging. 2015;40(7):2293-2305.

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