Management of intrahepatic cholangiocarcinoma: a review for clinicians

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy that arises from second-order biliary epithelial cells. Its incidence is gradually increasing worldwide. Well-known risk factors have been described, although in many cases, they are not identifiable. Treatment options are continuously expanding, but the prognosis of iCCA remains dismal. R0 liver resection remains the only curative treatment, but only a limited number of patients can benefit from it. Frequently, major hepatectomies are needed to completely remove the tumour. This could contraindicate surgery or increase postoperative morbidity in patients with chronic liver disease and small remnant liver volume. In cases of anticipated inadequate future liver remnant, regenerative techniques may be used to expand resectability. The role and extent of lymphadenectomy in iCCA are still matters of debate. Improvements in iCCA diagnosis and better understanding of genetic profiles might lead to optimized surgical approaches and drug therapies. The role of neoadjuvant and adjuvant therapies is broadening, gaining more and more acceptance in clinical practice. Combining surgery with locoregional therapies and novel drugs, such as checkpoint-inhibitors and molecular-targeted molecules, might improve treatment options and survival rates. Liver transplantation, after very poor initial results, is now receiving attention for the treatment of patients with unresectable very early iCCA (i.e. <2 cm) in cirrhotic livers, showing survival outcomes comparable to those of hepatocellular carcinoma. Ongoing prospective protocols are testing the efficacy of liver transplantation for patients with unresectable, advanced tumours confined to the liver, with sustained response to neoadjuvant treatment. In such a continuously changing landscape, the aim of our work is to review the state-of-the-art in the surgical and medical treatment of iCCA.

Keywords: chemotherapy; hepatectomy; intrahepatic cholangiocarcinoma; liver resection; liver transplantation; target therapy.

Figure 1.

Classification of intrahepatic cholangiocarcinoma (iCCA). Macroscopically, iCCA is classified into three subtypes, (1) mass-forming: iCCA with nodular/mass aspect; (2) periductal infiltrating: iCCA infiltrating along the bile duct; (3) intraductal growing: iCCA growing inside a bile duct. For each type, the corresponding pictures of the surgical specimens are detailed.

Figure 2.

Treatment algorithm for intrahepatic cholangiocarcinoma (iCCA). A traffic-light colour code defines the current approach for iCCA patients. *Also, in the presence of a single poor prognostic factors, such as elevated CA19.9 and/or CEA, size >75 mm, satellite nodules, possible R1v status, regional lymph node metastases (hepatic hilum or level 12). ^#Impossibility to achieve an R0/R1v resection preserving an adequate future liver remnant. ^†Consider severity of cirrhosis, level of portal hypertension, and cirrhosis-related complications. ^§Liver transplantation can be considered in very selected cases in the context of clinical studies. CA19.9 = carbohydrate antigen 19-9, CEA = carcinoembryonic antigen.

Figure 3.

Systemic therapy for intrahepatic cholangiocarcinoma (iCCA). The figure details the current systemic regimens in iCCA patients. *To be considered in frail patients.

Figure 4.

Research approaches used in the laboratory for intrahepatic cholangiocarcinoma. These approaches can be summarized in four areas: (1) 3D culture systems, such as tumouroids, organoids, and chip-systems; (2) biomarker discovery on circulating liquids or tissues; (3) metabolomic approaches; (4) immune-cells system analyses.