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Page 2 of 19 Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83

INTRODUCTION
Cholangiocarcinomas (CCAs) include a heterogeneous group of tumors that arise from the epithelial cells
of the bile ducts and, although rare, are highly lethal. In the United States, the annual incidence of CCA is
approximately 1.26 cases per 100,000 people, a rate that has significantly increased over the last two
[1,2]
decades . An estimated 9000 cases occur annually in the United States, and due to aggressive tumor
biology, low incidence of early detection, and poor efficacy of traditional therapies, less than 10% of all
[1,2]
patients diagnosed with CCA survive 5 years . While much work remains, recent improvements in
[2]
multimodality care have led to decreasing CCA mortality rates since 2013 .
In patients with CCA, surgical resection provides the only possibility for long-term survival. Unfortunately,
most cases of CCA are clinically silent, especially early in the disease process, commonly presenting with
locally advanced disease not amenable to resection . Advances in the surgical management of patients with
[3]
CCA (e.g., portal vein embolization, vascular reconstruction, locoregional and systemic therapies) have
expanded the pool of surgical candidates. For patients with resectable disease, median overall survival (OS)
is 51 months with a median relapse-free survival (RFS) of 24 months, significantly improved compared to
[4]
patients with the unresectable disease (median OS 11 months and median RFS 8 months) . However,
recurrence rates after surgical resection remain high (> 60%) . In this article, we review the evaluation and
[5]
treatment of CCA with a focus on the surgical management of CCA.

Classification
CCA classification includes intrahepatic, perihilar, and extrahepatic or distal subtypes. Approximately 50%
arise from perihilar ducts, 40% from distal ducts, and less than 10% from intrahepatic ducts . Anatomically,
[6]
intrahepatic cholangiocarcinoma (ICCA) arises from the segmental bile ducts or smaller branches of the
intrahepatic biliary tree [Figure 1] . Per the 2019 WHO classification of tumors of the digestive system,
[7]
ICCA has two main subtypes: large duct type, which resembles extrahepatic cholangiocarcinoma, and small
duct type, which shares many characteristics with hepatocellular carcinoma . Perihilar cholangiocarcinoma
[8]
(PCCA) arises from the cystic duct-common duct junction to the second-order bile ducts . Distal
[9]
cholangiocarcinoma (DCCA) develops between the ampulla of Vater to the cystic duct . However, some
[9]
debate exists about the exact transitions between the CCA subtypes. Multiple classification systems exist for
CCA, each with its own limitations. A well-known staging system by The American Joint Committee on
Cancer (AJCC) stratifies disease prognosis by stage based on tumor size (T), lymph node disease (N), and
[10]
metastasis (M) for the three subtypes of CCA . The Bismuth-Corlette classification further subdivides
perihilar tumors by the extent of ductal infiltration . Type I PCCAs include tumors distal to the confluence
[11]
of the left and right ducts; type II tumors involve the confluence; type III tumors extend into the right
hepatic duct (IIIa) or left hepatic duct (IIIb) in addition to involving the confluence; type IV tumors extend
into both the right and left hepatic bile ducts. An alternative classification system for PCCAs, the Blumgart
staging system, includes clinically relevant factors such as the presence or absence of portal venous invasion
and hepatic atrophy in addition to tumor location and extent of bile duct involvement [12,13] . This system
classifies tumors into three stages (T1-T3) and predicts resectability, the potential for metastatic disease, and
survival [12,13] . As understanding of the complex pathophysiology of CCA improves, new classification
systems will continue to emerge; however, as of now, no universally accepted system exists [14-17] .

Risk factors
Large population-based studies have revealed several risk factors for CCA. While metabolic conditions (i.e.,
obesity, diabetes, and nonalcoholic fatty liver disease) and toxic exposures (i.e., alcohol, tobacco, 1,2-
dichloropropane, dichloromethane, and thorotrast) are known risk factors for CCA [18-23] , chronic
inflammation of the bile ducts is associated with most cases of CCA. In the Western world, the etiology of
long-standing bile duct inflammation includes primary sclerosing cholangitis (PSC) and choledochal cystic