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Ruff et al. Hepatoma Res 2023;9:17 https://dx.doi.org/10.20517/2394-5079.2023.18 Page 3 of 12

Figure 1. Hepatocellular carcinoma (lower panel) versus intrahepatic cholangiocarcinoma (upper panel) on computed tomography
imaging [17] . The figure was reprinted from reference 17 with permission.

Hypovascular ICCAs commonly have lymphatic, perineural, or biliary invasion and worse overall survival,
[19]
whereas hypervascular tumors have a lower incidence of invasion and better long-term survival . MRI
better detects locoregional spread of ICCA and can be used to further differentiate ICCA from HCC.
Diffusion-weighted images often demonstrate rim enhancement during the arterial phase, also known as the
target sign in ICCA .
[20]

FDG-PET may help ascertain the presence of intra- and/or extrahepatic disease including lymph node
metastasis. ICCA is an FDG avid tumor, so FDG-PET in the preoperative setting should be considered, but
there may be a risk of false positives in the setting of chronic inflammation. FDG-PET can sometimes help
identify occult metastasis, which can result in a shift in the proposed treatment plan (i.e., use of preoperative
[21]
chemotherapy) or change determinations of resectability .
UPFRONT SURGERY VERSUS NEOADJUVANT CHEMOTHERAPY
Currently, surgery offers the best potential for cure among patients with ICCA . Unfortunately, even after
[22]
resection, recurrence ranges from 42-70% [3,23,24] . Patients who present with resectable ICCA generally can
proceed to upfront surgery with consideration of adjuvant capecitabine in the postoperative period. In the
phase III clinical BILCAP trial, patients with ICCA were randomized to either adjuvant capecitabine or
observation after curative resection . The trial did not meet its primary endpoint, but did demonstrate
[3]
improved overall survival in the capecitabine cohort (51.1 months) compared with the observation cohort
(36.4 months).

Among patients with locally advanced ICCA who are not candidates for resection, chemotherapy with
gemcitabine and cisplatin is typically employed. In fact, gemcitabine and cisplatin have been the standard-
of-care first-line therapy for metastatic and locally advanced ICCA for the past decade based on the phase
[6]
III ABC-02 clinical trial . Following treatment with chemotherapy, patients should be re-imaged/staged as
a subset may have disease cytoreduction and subsequently be candidates for hepatectomy. In conjunction
with liver-directed therapies, chemotherapy can sometimes downstage/downsize ICCA to make it more
amenable to resection from a technical/anatomic standpoint [25,26] . One retrospective study reported that 53%
of patients with locally advanced ICCA were downstaged/downsized and were able to undergo resection;
there was no difference in median overall survival between the downstaged/downsized patients versus
patients who had upfront resectable ICCA . A separate retrospective study similarly demonstrated that
[25]
36.4% of patients with advanced, unresectable ICCA became surgical candidates after preoperative
chemotherapy and half of the patients who underwent resection had an R0 margin . In addition, among
[26]