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16 Digital Diagnosis andManagement ofCholangiocarcinoma
a
b
367
Fig. 16.5 ICC gross pathological classication. (a) Mass forming; (b) Periductal inltration; (c) Intraductal growth; (d) Mixed
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F. Shen et al.
c
d
Fig. 16.5 (continued)
include adenocarcinoma, adenosquamous cell carcinoma,
squamous cell carcinoma, mucinous carcinoma, and signet
ring cell carcinoma. The majority of ICC are adenocarcinoma with different degrees of differentiation, which can be
divided into high, medium, and low differentiation (Li 2013).
16.2.2.4 Clinical Staging
Currently, there are various ICC staging systems, most of
which are based on Western patients. Moreover, the main difference lies in the difference of T grading. AJCC/UICC staging system (version 7) is a vital tool. Its independent staging
of ICC from HCC is a signicant improvement over the old
staging system that considers both hepatocellular carcinoma
and ICC as “primary liver cancer”. Also, the seventh edition
no longer regards tumor size as a prognostic factor, but the
number of lesions, vascular invasion, intrahepatic metastasis,
and adjacent tissue inltration as important factors affecting
T grade (Edge and Compton 2010). The eighth edition of
AJCC was published in October 2016 and has been available
worldwide since January 01, 2018 (Table16.1). The update
of the eighth edition mainly focuses on the revision of
T-stage, which has a greater guiding signicance for prognosis and stronger clinical operability (Mahul etal. 2016). At
present, based on the Eastern population and TNM staging,
there are several ICC staging systems, including the
Okabayashi staging system (Okabayashi etal. 2001), Liver
Cancer Study Group of Japan (LCSGJ) staging system
(Shaib et al. 2005), Chinese Fudan University prognosis
16 Digital Diagnosis andManagement ofCholangiocarcinoma
369
Table 16.1 AJCC cancer staging manual (eighth edition)
Intrahepatic cholangiocarcinoma:
Primary Tumor (T)
Tis Carcinoma in situ
T1a Solitary tumor without vascular invasion, ≤5cm
T1b Solitary tumor without vascular invasion, >5cm
T2 Solitary tumor with vascular invasion; Multiple tumors, with
or without vascular invasion
T3 Tumor perforating the visceral peritoneum or involving the
local extrahepatic structures by direct invasion
T4 Tumor with periductal invasion
Regional Lymph Nodes (N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis present
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis present
TNM staging
Stage 0 Tis, N0, M0
Stage IA T1a, N0, M0
Stage IB T1b, N0, M0
Stage II T2, N0, M0
Stage IIIA T3, N0, M0
Stage IIIB T4, N0, M0
Any T, N1, M0
Stage IV Any T, Any N, M1
scoring system (Jiang etal. 2011), etc., as well as survival
charts after ICC hepatectomy in the Eastern Hepatobiliary
Surgery Hospital.
16.2.3 Surgical Treatment ofICC
16.2.3.1 Preoperative Assessment
Liver Function Assessment
Serum albumin and total bilirubin levels can be used to predict the risk of postoperative liver failure. Preoperative albumin <3 g/dl and bilirubin >10 mg/dl often indicate poor
prognosis of ICC patients (Mosconi etal. 2009). Preoperative
biliary drainage can reduce the level of bilirubin and reduce
the incidence of postoperative hepatic insufciency in
patients with jaundice who are carefully evaluated for hilar
bile duct invasion and underwent R0 resection. For patients
with less than 30% of the residual liver volume, preoperative
chemoembolization is feasible to promote the compensatory
proliferation of residual liver and reduce postoperative complications and mortality (Nagino etal. 2006).
Resectability Assessment
The prognosis of ICC patients is closely related to the possibility of radical resection, but the radical resection rate is
only 15%~20%, which is far lower than 70% for distal cholangiocarcinoma (Poultsides etal. 2010). In radical surgery, it
is crucial to ensure complete tumor resection and no invasion
of tumor cells at the surgical margin. Criteria for tumor
resection include intrahepatic and extrahepatic bile duct
invasion, vascular invasion, hepatic lobe atrophy, and local
and distant metastasis. Preoperative clinical and imaging
data of ICC patients should be fully collected to assess the
feasibility of radical resection, and physical status score,
nutritional status, and disease status should also be taken into
account. ICC invasion of secondary and higher bile duct
branches is considered a contraindication for surgical
removal. Portal vein invasion is an independent risk factor
for advanced tumors, but many risk factors, such as peritoneal metastasis, intrahepatic metastasis, lymph node metastasis, and the extent of actual tumor invasion, can only be
accurately dened by abdominal exploration (Bagante etal.
2016). Imaging examinations, including abdominal CT and
various forms (MR, endoscopy, or transhepatic cholangiopancreatography) contribute to the diagnosis and staging of
ICC.Positron emission tomography (PET) can detect potential occult metastasis. About 36% of patients with intrahepatic or peritoneal metastases were inoperable by laparoscopy
(Goere etal. 2006). Intraoperative ultrasound combined with
laparoscopy can be used to detect intrahepatic metastasis and
vascular inltration.
3D Visualization Assessment
With the development of imaging technology and computer
digitization technology, 3D imaging technology based on CT
or MRI is becoming more and more mature, and ICC preoperative evaluation also plays a vital role. Three-dimensional
imaging can assist surgeons in a more accurate surgical
design. For example, it is challenging to make an individualized evaluation accurately based on two-dimensional imaging (CT, MRI) because the individualization of hepatic vein
branches is quite varied. Therefore, surgical planning based
on two-dimensional images is uncertain. 3D images of liver
contour, tumor location, and size, hepatic vein system, etc.
can be used to show the involvement of the tumor in the
hepatic segment and to view the course of the intrahepatic
vessels in an all-round way by using a 3D reconstruction system. It is also possible to predict important vascular structure
and its inuence on the operation by using software to simulate the surgical approach and even to predict the length of
the upper incisor edge in each direction. Also, 3D reconstruction imaging can diagnose portal vein invasion. The
portal vein invasion can be identied by evaluating the drainage area of each portal vein under 3D visualization. It can
even be used to determine whether to dissect or retain a portal vein before an operation (Takahashi et al. 2010).
Postoperative liver failure and residual liver failure are still
the leading causes of mortality after hepatectomy in ICC,
especially in patients with advanced ICC (Jonas etal. 2009).
Three-dimensional reconstruction software can automatically calculate tumor volume, resected liver volume, and
residual liver volume. It is essential to evaluate the residual
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F. Shen et al.
Fig. 16.6 CT images of case 1
liver volume after ICC hepatectomy, especially for the
patients with ICC invading the hilar bile duct and other
important duct structures. The method is simple, and the
error rate is less than that of the two-dimensional imaging
results. At the same time, combined with the results of preoperative ICG 15-min retention test (ICG-R15), it is very
important to accurately evaluate the residual liver volume
after ICC hepatectomy, especially for the ICC invading
important pipeline structures such as bile duct of the hepatic
portal vein.
Case 1 was a patient with left intrahepatic cholangiocarcinoma. CT showed that the left inner lobe, left lateral
lobe, and right anterior lobe were invaded, and the residual
liver volume might be insufcient after resection
(Fig. 16.6). After three-dimensional reconstruction, the
liver volume was measured as 2158.96 ml, excluding
1058.25 ml of right hepatic volume. No tumor invasion
was found in the right portal vein, right hepatic artery, and
right hepatic vein (Fig. 16.7). Left trilobectomy+ cholecystectomy was performed, and the patients recovered
well after surgery.
Case 2 was a patient suspected of abdominal space occupying. CT indicated that the tumor was located between the
liver and the stomach, and abdominal malignant tumors
could not be excluded (Fig. 16.8). Three-dimensional
reconstruction suggested that the tumor was located in the
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371
Fig. 16.7 3D reconstruction of case 1
left lateral lobe of the liver, invading into the abdominal
cavity (Fig.16.9). A left hepatectomy was performed, and
postoperative pathology showed left intrahepatic
cholangiocarcinoma.
Case 3 was also a patient with left intrahepatic cholangiocarcinoma. CT indicated that the tumor was located in
the left inner lobe of the liver and invaded the left and right
portal vein bifurcation, which may be unresectable
(Fig.16.10). After three-dimensional reconstruction, it was
suggested that there was no invasion of the right portal vein
and right hepatic artery. A left hepatectomy was successfully performed (Fig.16.11).
16.2.3.2 Surgical Approach
According to the size and location of the tumors, conventional hepatectomy should be performed as far as possible,
such as segmentectomy, left, and right hepatectomy. Because
ICC is often associated with lymph node metastasis,
intraoperative lymph node metastasis was routinely explored.
We still consider lymphadenectomy as a routine procedure
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F. Shen et al.
Fig. 16.8 CT images of case 2
for ICC surgery, although it is controversial. For some tumors
located adjacent to the hilum of the liver, extrahepatic cholangiectomy, choledochojejunostomy, and caudate lobectomy
are required.
16.2.3.3 Controversial Point
Lymphadenectomy
Lymph node metastasis is an important factor affecting the
prognosis of ICC, but the need for routine lymphadenectomy
is still controversial. There are a few studies of this. Some
studies show that routine lymphadenectomy can reduce the
local recurrence for ICC patients (Jutric etal. 2016; Morine
and Shimada 2015). Given the high incidence of lymph node
metastasis in ICC, regional lymphadenectomy was recommended in 2015 by ICC therapists as a standard part of the
operation in order to reduce the local recurrence of lymph
node metastasis (Weber etal. 2015). Although lymph node
metastasis is an important prognostic factor of ICC, lymphadenectomy does not seem to bring signicant survival benets to patients. Therefore, there is still a lack of consensus
on whether to use it as a routine treatment (Edge etal. 2010;
de Jong etal. 2011). There is evidence that the lymphadenectomy group failed to achieve a better prognosis compared
with the control group, and especially for some advanced
and metastatic lesions, lymphadenectomy could not
completely remove the lesions outside the eld of vision,
resulting in a poor prognosis. Lymph node metastasis has a
negative impact on the prognosis, and the rate of ICC lymph
node metastasis is as high as 40%. Even some pathological
studies show that 55% of patients have at least one regional
lymph node invasion (Endo etal. 2008; de Jong etal. 2011).
16 Digital Diagnosis andManagement ofCholangiocarcinoma
373
Fig. 16.9 3D reconstruction of case 2
According to our experience, lymphadenectomy should be
carried out regardless of whether the lymph nodes were
detected before or during the operation. Even if the postoperative pathological examinations were negative, it would be
helpful to guide the clinical staging and postoperative treatment. Nevertheless, we need to pay attention to the potential
risks of lymphadenectomy, especially that at the hepatic
hilum. The benets and possible complications could be
evaluated by using pre-operative three-dimensional imaging
techniques.
Extended Hepatectomy
Complete surgical resection of the tumor is an important
guarantee for a good prognosis. For ICC patients, this means
anatomical hepatectomy or combined resection of vascular
structures and peripheral organs. It has been reported that
large tumor size, intrahepatic metastasis, lymph node metastasis, and vascular invasion are associated with poor prognosis after ICC resection. Unlike patients with hepatocellular
carcinoma, the prognosis of ICC patients with a wide margin
of resection is signicantly better than that of patients with a
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F. Shen et al.
Fig. 16.10 CT images of case 3
narrow margin of resection. Therefore, patients with ICC and
large-diameter tumors need to achieve R-0 resection with as
wide a margin of resection as possible. Some studies have
demonstrated that extended hepatectomy is safe and effective for certain large diameter or multiple ICC (Spolverato
et al. 2015a, b). Spolverato et al. (2015a, b) reported 557
cases of ICC patients resected surgically, and they set group
A (215 cases) for those with tumors smaller than 7cm and
single tumor, and group B (342 cases) for those with relatively advanced tumors. The results showed that the proportion of patients receiving extended hepatectomy in group B
was lower than that in group A (30.4% vs. 16.9%, P<0.001),
and postoperative pathology showed that vascular invasion,
adjacent organ invasion, and lymph node metastasis were
more common in group B than in group A.The incidence of
postoperative complications and hospitalization mortality
were similar between the two groups. Patients in group A
showed better 5-year and disease-free survival (DFS) than
those in group B. For patients with multiple tumors (3 or
more) or lymph node metastasis, especially for patients with
abdominal trunk and para-aortic lymph node metastasis, the
indications for extended hepatectomy should be carefully
evaluated, and adjuvant treatments such as chemotherapy
and interventional therapy can be considered before surgery
(Tabrizian et al. 2015). Therefore, even if the relationship
between surgical margin and prognosis of ICC remains controversial (Tabrizian et al. 2015; Tamandl et al. 2008;
Murakami etal. 2014; Spolverato et al. 2015a, b), we still
16 Digital Diagnosis andManagement ofCholangiocarcinoma
375
Fig. 16.11 3D reconstruction of case 3
recommend that anatomical hepatectomy should be carried
out as far as possible provided the stipulated conditions for
residual liver are satised according to the preoperative 3D
imaging. When complete resection is not feasible or residual
liver is insufcient, the surgical margin of 1cm should be
guaranteed as far as possible.
Combined vascular resection is also one of the strategies
for R0 resection, and such resection is required in 9%–14%
of patients with radical hepatectomy (Endo etal. 2008; Ali
etal. 2013; Weber etal. 2001). Vascular resection, combined
with hepatectomy, increases the possibility of a negative surgical margin (Dodson et al. 2013). Therefore, in order to
achieve R0 resection in some evaluated patients, hepatectomy combined with resection and reconstruction of the
inferior vena cava and portal vein is feasible. Hepatectomy
combined with visceral resection involves the removal of
adjacent organs such as the gallbladder, extrahepatic bile
duct, diaphragm, and pancreas (Endo et al. 2008; Nathan
etal. 2007; Konstadoulakis etal. 2008; Hanazaki etal. 2002;
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F. Shen et al.
Hyder etal. 2013). However, further clinical data are needed
to conrm the long-term efcacy of such resection.
Liver Transplantation
Liver transplantation (LT) is not recommended as a routine
option for ICC due to the lack of indications and the highly
controversial nature of its use (Bridgewater etal. 2014). ICC
liver transplantation is no longer performed in many centers
due to low long-term survival and high recurrence rates.
However, some recent studies have shown that ICC patients
with a single small tumor can achieve satisfactory long-term
survival after liver transplantation (Facciuto et al. 2015;
Hashimoto and Miller 2015). ICC patients who received
liver transplantation had a 3-year survival rate of 50%–65%
without further adjuvant therapy (Fu etal. 2011; Sotiropoulos
etal. 2008), while those who received systemic chemotherapy or neoadjuvant therapy had a better survival rate (Hong
etal. 2011). The common adverse prognostic factors of liver
transplantation include the history of nerve invasion, multifocal inltration, and lymphatic invasion. At the same time,
studies (Sapisochin etal. 2014a, b) have found that certain
ICC patients, especially small single tumors or welldifferentiated patients, can have better long-term survival
after liver transplantation, while in contrast, moderately differentiated ICC has a high recurrence rate and poor survival
(Takahashi etal. 2016). In summary, liver transplantation is
not completely ineffective, but its controversial indications
and low cost-effectiveness may limit its use in ICC therapy.
Operative Prognosis
The 5-year overall survival rate (OS) of ICC patients after R0
resection was 15%~ 40%, of which 80% have an intrahepatic recurrence (Bridgewater etal. 2014; Hyder etal. 2014),
and the prognosis is signicantly worse than that of hepatocellular carcinoma, which may be due to the histological difference between HCC and ICC, lymph node, nerve, hepatic
portal vein, hepatic portal vein invasion. Lymph node metastasis accounted for 85%, 80%, 58%, 40%, and 37%, respectively, which is similar to hilar cholangiocarcinoma and
distal cholangiocarcinoma (Shirai etal. 2008). The ratio of
intrahepatic portal vein invasion, hepatic vein invasion, and
intrahepatic metastasis is similar to that of HCC (Endo etal.
2008; Choi etal. 2009; Ellis etal. 2011). The incidence of
postoperative complications is 11% to 58%, including biliary leakage, liver dysfunction, abdominal infection, and portal vein embolism. The perioperative mortality rate ranges
from 1.2% to 7%. The most common causes are liver failure,
septic shock, and multiple organ dysfunction. In conclusion,
ICC has similar characteristics to HCC and cholangiocarcinoma, but the prognosis is poor (Ali etal. 2013; Lang etal.
2009; Dhanasekaran etal. 2013).
Some studies have reported improvements in ICC survival over the past few years, but they note that this change
may be due to advances in some nonsurgical treatments and
careful screening of surgical patients (Yamamoto et al.
1999). The prognosis of ICC patients depends largely on
tumor stages (especially lymph node involvement and vascular invasion) rather than size and surgical margin (Carpizo
and D’Angelica 2009; Sasaki etal. 1998). The 5-year postoperative survival rate is generally about 40% (Puhalla etal.
2005; Maithel etal. 2013). In patients with negative surgical
margins (R0 resection) and no lymph node invasion, the survival rate can be as high as 63% (Weber et al. 2001; Paik
etal. 2008; Mavros etal. 2014). A French study of 163 ICC
patients undergoing radical surgery reported that the overall
5-year survival rate was 32%. The 5-year overall survival
rates based on the seventh AJCC staging were 62% in stage I
(T1N0), 27% in stage II (T2N0), and 14% in stage III (T3N0,
T1–3, N1) (Clarke 2000). Portal vein carcinoma thrombi
have been shown to be an independent risk factor for survival
in ICC patients undergoing hepatectomy (HR = 1.783;
95%CI: 1.28~2.49) (Lu etal. 2016). A retrospective study
of 74 patients undergoing ICC surgery indicated that a return
to normal postoperative CA19-9 levels predicted good survival (Yoo etal. 2015). Propensity score matching analysis
showed that a nomogram was a better method to predict
postoperative survival. A prognostic nomogram of ICC has
been proposed, incorporating tumor (T) and lymph node (N)
grades, tumor size, tumor number, preoperative serum tumor
marker levels, and microvascular invasion (Bridgewater
etal. 2014). A multicenter retrospective study showed that
the long-term prognosis of the elderly after hepatectomy was
similar to that of the young, but the incidence of their postoperative complication was higher.
Recurrence is an important factor affecting the prognosis
of ICC patients. Even in patients with radical resection of
ICC, the 5-year recurrence rate was reported to be as high as
79% (Dodson etal. 2013). Local recurrence is the most common pattern, and other patterns include intrahepatic, lymph
node, or extrahepatic (peritoneal) recurrence/metastasis
(Hasegawa et al. 2007; Zhu and Knox 2012). The study,
based on an international database, observed 563 patients
with ICC undergoing radical resection and followed up regularly. The median follow-up time was 19 months. It was
found that the most common recurrence sites were intrahepatic (59.8%), extrahepatic (14.5%), and intrahepatic plus
extrahepatic recurrence (25.7%) (Spolverato et al. 2016).
Unlike hepatocellular carcinoma, which mainly occurs in the
liver, ICC recurrence is more systemic (Bridgewater etal.
2014; Choi etal. 2009; Yamamoto etal. 2001). The progno-
sis of recurrent ICC patients was very poor, with a mean survival time of 26.7months after reoperation, and 11.1months