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Page 2 of 12 Ruff et al. Hepatoma Res 2023;9:17 https://dx.doi.org/10.20517/2394-5079.2023.18

[1]
tracts within the liver and accounts for approximately 10% of CCAs . ECCA is divided into either hilar
(Klatskin) CCA arising from the common hepatic duct or distal ECCA arising from the common bile duct
[1]
below the insertion of the cystic duct down to the level of the ampulla of Vater . There is increasing
evidence to suggest that ICCA and ECCA are biologically different and should be treated as different
cancers .
[2]
The standard of care for patients with resectable ICCA at diagnosis is upfront surgery with adjuvant
capecitabine . Unfortunately, only approximately 15% of patients with ICCA present with resectable
[3]
disease at the time of diagnosis, and even among individuals who undergo surgery and adjuvant
capecitabine, there is a high rate of recurrent and metastatic disease . Median overall survival is between 27
[4]
and 36 months for these patients . For patients with advanced or metastatic disease at diagnosis, the
[5]
combination of gemcitabine and cisplatin chemotherapy is currently the standard of care based on the
ABC-02 trial . In addition, for patients with ICCA, liver-directed therapy (e.g., hepatic artery infusion
[6]
pump, Yttrium-90 radioembolization) can be used in combination with systemic therapy . Given the poor
[7]
prognosis of ICCA, research and clinical trial efforts have been focused on developing effective targeted
[8]
therapy through molecular profiling of the tumor to target specific genetic aberrations .

For patients with resectable disease, upfront surgery is the best chance of cure. The goal of surgery for ICCA
is to perform a margin-negative resection and regional lymphadenectomy with at least six lymph nodes
harvested, and minimize the risk of complications or hepatic insufficiency. We herein review the critical
aspects of the surgical management of ICCA to obtain a successful oncologic outcome.

DIAGNOSTIC WORK UP
While patients with extrahepatic CCA present with biliary obstruction (jaundice, pruritus, dark urine, light
colored stool), patients with ICCA more commonly present with abdominal pain, generalized malaise, or
weight loss. Abdominal pain is caused by displacement of the hepatic parenchyma stretching the liver
capsule. Unfortunately, many patients who present with symptoms already have advanced disease, and
given the frequently asymptomatic presentation or vague symptoms associated with ICCA, many
[9]
individuals are diagnosed late in the course of disease . A small subset of patients who have large ICCA
tumors that encroach on the hepatic hilum can present with jaundice and hyperbilirubinemia, requiring
biliary stenting. Risk factors for ICCA include primary sclerosing cholangitis, fibropolycystic liver disease,
intrahepatic biliary stones, carcinogen exposure (e.g., 1,2 dichloropropane or dichloromethane from
occupational exposure in the printing industry), and chronic inflammation secondary to hepatitis B or
C [10-12] . Tumor markers like carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and
alpha-fetoprotein (AFP) can help physicians narrow the differential diagnosis. Patients with ICCA are more
likely to have an elevated CA19-9, while hepatocellular carcinoma (HCC) is associated with an elevated
AFP. CA19-9 and CEA have also been reported to have prognostic value in ICCA [13,14] .

Imaging is key to defining the diagnosis. While ultrasound is traditionally the initial modality to rule out
common benign etiologies of right upper quadrant pain or biliary obstruction, contrast-enhanced computed
tomography (CT) scans and/or magnetic resonance imaging (MRI) are the preferred methods to image
hepatic pathology, define tumor extension, and evaluate resectability. HCC arises from the hepatocytes and
will often demonstrate an arterial enhancement pattern on CT scan. In contrast, ICCA arises from hepatic
parenchyma with desmoplastic features and its main blood supply is the portal system. In turn, ICCA is
typically characterized by peripheral rim-like contrast enhancement during the arterial and portal phases
and a more attenuated center during the delayed phase [Figure 1] [15-18] . ICCA has three patterns of
enhancement that correlate with different tumor biology: hypovascular, rim-like, and hypervascular.