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Page 2 of 13 Bale et al. Hepatoma Res 2023;9:44 https://dx.doi.org/10.20517/2394-5079.2023.71

INTRODUCTION
Incidence of iCCA
Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with a
worldwide increase in incidence and mortality. Due to its late diagnosis, aggressive biology, and resistance
[1]
to therapy, iCCA is generally associated with a poor 5-year OS of less than 10% .
Histopathology and risk factors for iCCA
The large and small duct types of iCCA exhibit different clinicopathological characteristics and mutation
profiles . Small duct iCCA is frequently associated with non-biliary chronic liver illnesses, such as viral
[2]
hepatitis and metabolic syndrome. The large duct iCCA type occurs in chronic cholangitis and is
characterized by more severe pathological symptoms like lymphatic and/or perineural invasion, and a worse
[3]
long-term prognosis . Primary sclerosing cholangitis (PSC) is the most important known risk factor for
iCCA, which is an important cause of death among PSC patients . Annually, approximately 0.6%-1.5% of
[4]
PSC patients develop iCCA, with a prevalence of 6 to 13% and a lifetime risk of up to 20% .
[5]
Diagnosis of iCCA
According to the recent EASL guidelines , a tumor biopsy is recommended in order to confirm the iCCA
[6]
diagnosis, distinguish subtypes, and investigate molecular parameters. In terms of imaging, MRI is superior
to CT to stage iCCA within the liver . Distinguishing iCCA from cHCC-iCCA (combined hepatocellular-
[7]
cholangiocarcinoma), which is characterized by both hepatocytic and cholangiocytic phenotypes, remains a
difficult task . Therefore, if there are multiple suspicious nodules with varying imaging characteristics, we
[8]
recommend biopsies of at least one nodule with each different imaging appearance. PET scanning is
recommended to identify metastatic lymph nodes and distant metastases. PET scan has a sensitivity and
[7]
specificity of 37% and 97%, respectively, to detect lymph node metastasis . In addition, endoscopy-guided
[9]
lymph node sampling may be helpful to inform treatment decisions .
Treatment options for iCCA
Surgical resection
According to recent guidelines [10-12] surgical resection (SR) with negative margins (R0) remains the first-line
treatment for iCCA. However, only 12%-40% of patients who are referred for treatment are resectable [13,14] .
Reported overall survival (OS) at 5 years ranges from 22% to 45%, and recurrence rates are as high as
[15]
80% . Due to the early and high incidence of tumor recurrence in the postoperative setting, multifocal
iCCA portends a poorer prognosis versus solitary lesions . Recently, liver transplantation (LT) was
[6]
proposed as an alternative to SR in cirrhotic patients with small iCCA. In a retrospective multicenter
study , 49 LT and 26 SR patients with iCCA/cHCC-CCA ≤ 5 cm in cirrhosis were compared. LT patients
[16]
had a markedly lower incidence of recurrence (18% vs. 46%; P = 0.01). Among patients in the LT group, 5-
year survival was 69% and 65% (P = 0.40) among patients with lesions ≤ 2 cm and > 2-5 cm, respectively. In
another retrospective analysis, 1-, 3-, and 5-year actuarial survival of 82%, 61%, and 61% were achieved in
six patients with single tumors up to 3 cm . According to the most recent EASL guidelines, early-stage
[17]
iCCA ( ≤ 3 cm) arising in the context of cirrhosis is eligible for liver transplantation, preferably under study
[6]
protocols .
Systemic treatment
In two randomized controlled trials, the combination of gemcitabine and cisplatin (GemCis) was associated
with a median OS of 11.6 months . GemCis is currently the standard first-line treatment for patients with
[18]
advanced iCCA. The addition of durvalumab to GemCis increased the median OS to 12.8 months among
patients with good performance status . Immune checkpoint inhibitors and molecularly targeted therapies,
[19]
which may have the potential to revolutionize systemic treatment of iCCA, are being tested in multiple