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Page 4 of 19 Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83

DIAGNOSTIC WORKUP
CCA commonly presents with non-specific symptoms such as abdominal pain, weight loss, fatigue, and
[9]
night sweats . While ICCAs usually remain asymptomatic until the mass is significantly large to cause mass
effect, PCCAs and DCCAs can cause biliary obstruction producing earlier symptoms such as jaundice,
pruritis, dark-colored urine, and clay-colored stools. Once suspected, workup of CCA includes a
multiphasic abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (MRI) with IV
contrast, chest CT, liver function tests, tumor markers CEA, CA 19-9, ± Alpha-fetoprotein and
[47]
EUS/biopsy . Since most pathologic hepatic lesions are metastatic in origin, additional workup to include
an esophagogastroduodenoscopy, colonoscopy, and mammography are strongly encouraged before a
definitive diagnosis of ICCA is made [47,48] . Fluorodeoxyglucose-positron emission tomography can be helpful
to rule out distant metastatic disease . MRI/magnetic resonance cholangiopancreatogra (MRCP) is
[49]
emerging as the preferred imaging modality, especially for the evaluation of ICCA and PCCA .
[28]
MRI/MRCP offers a comparable evaluation of the biliary system to endoscopic retrograde
cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography in addition to enabling
the surgeons to examine vascular involvement and local tumor extension, knowledge of which is critical in
determining resectability and surgical approach . All patients with CCAs should be reviewed by a
[50]
multidisciplinary team. In cases where the diagnosis is in doubt (e.g., biliary stricture with negative
brushings), surgical resection should be considered on an individual patient basis as certain clinical
scenarios may be consistent with an oncologic etiology despite the lack of a tissue diagnosis.

Once the diagnosis is established, resectability drives the prognosis for patients with CCA. Guidelines vary,
but traditional criteria for resectability include the absence of retropancreatic or paraceliac lymph node
involvement, absence of extrahepatic adjacent organ invasion, absence of disseminated disease, and absence
of main portal vein or main hepatic artery invasion; however, certain specialized, high volume centers have
acceptable outcomes with en bloc resection of the portal vein or hepatic artery followed by vascular
reconstruction if microscopically negative margins (R0 resection) are achieved [51-55] . Additional factors for
resection are specific to the tumor location and include bilateral duct involvement up to secondary radicles,
atrophy of one lobe with contralateral secondary biliary radicle involvement, or involvement of bilateral
[56]
hepatic arteries . Staging laparoscopy provides limited benefit in the evaluation of locoregional
involvement due to the improvement in cross-sectional imaging, but it can be used selectively to rule out
small peritoneal disease in high-risk patients such as those with elevated CA 19-9 levels in the absence of
biliary obstruction .
[57]
Preoperative optimization
Preoperative biliary decompression in CCA remains controversial [58-63] . Data from recent meta-analyses have
come to different conclusions on the impact of preoperative stenting [62,63] . Proponents of preoperative biliary
decompression cite the physiologic impact of hyperbilirubinemia on liver regeneration and immune
function, as well as the potential increase in postoperative complications . Preoperative biliary drainage is
[64]
indicated in patients with severe symptomatic jaundice, cholangitis, or in patients with hyperbilirubinemia
and planned chemotherapy . Opponents argue that the procedure itself (i.e., endoscopic or percutaneous
[65]
approach) can have complications such as bleeding or perforation as well as future complications from stent
or drain blockage. Furthermore, unnecessary manipulation of the biliary tract may lead to cholangitis and
sepsis . When preoperative drainage is pursued, the interval of drainage (i.e., time from drainage
[64]
procedure to surgery) should be short to decrease the risk of complications. Furthermore, debate continues
surrounding the optimal approach for preoperative drainage, endoscopic versus percutaneous [66-68] . A recent
multicenter randomized controlled trial examining these two approaches was stopped early due to higher
all-cause mortality in the percutaneous transhepatic biliary drainage group; however, the results were hard
to interpret due to low study enrollment . Well-powered randomized controlled trials are needed to
[69]