Incidental Gallbladder Cancer

Abstract

Gallbladder cancer (GBC) is a rare but fatal disease with an incidence of less than 5000 new cases per year in the United States. Less than 20% of GBC cases are diagnosed preoperatively. The remaining cases are diagnosed either after laparoscopic cholecystectomy or intraoperatively. GBC is discovered incidentally during histopathology following 0.25–3.0% of laparoscopic cholecystectomies; however, this constitutes 74–92% of all GBC. The most pivotal and important step is accurate patient staging. Staging dictates disease management and treatment options and predicts survival. Because of the fatality of GBC and its poor prognosis, attempts of curative surgery are limited to localized resectable disease.

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Chapter 6
Incidental Gallbladder Cancer
Faisal Al-alem, Rafif E. Mattar, Ahmad Madkhali,
Abdulsalam Alsharabi, Faisal Alsaif and
Mazen Hassanain
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/67654
Provisional chapter
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.
Incidental Gallbladder Cancer
Faisal Al-alem, Raf E. Mattar,
Ahmad Madkhali, Abdulsalam Alsharabi,
Faisal Alsaif and Mazen Hassanain
Additional information is available at the end of the chapter
Abstract
Gallbladder cancer (GBC) is a rare but fatal disease with an incidence of less than 5000
new cases per year in the United States. Less than 20% of GBC cases are diagnosed preop-
eratively. The remaining cases are diagnosed either after laparoscopic cholecystectomy
or intraoperatively. GBC is discovered incidentally during histopathology following
0.25–3.0% of laparoscopic cholecystectomies; however, this constitutes 74–92% of all
GBC. The most pivotal and important step is accurate patient staging. Staging dictates
disease management and treatment options and predicts survival. Because of the fatal-
ity of GBC and its poor prognosis, aempts of curative surgery are limited to localized
resectable disease.
Keywords: gallbladder, cancer, incidental, adenocarcinoma
1. Introduction
Laparoscopic cholecystectomy is the most common elective operation performed worldwide.
It is the standard of care for all symptomatic gallstone diseases. Gallbladder cancer (GBC) is
a rare but fatal disease with an incidence of less than 5000 new cases per year in the United
States. The anatomy of the gallbladder, specically the absence of a serosal layer between it
and the liver, permits the relative early invasion of GBC into the liver [1]. GBC also tends to
spread both to lymph nodes and hematogenously to the peritoneal surfaces [2]. Moreover,
because of its nonspecic presentation and constellation of symptoms and signs, many of
which it shares with benign diseases such as biliary colic or chronic cholecystitis, GBC tends
to go undiagnosed until relatively later stages [2]. Less than 20% of GBC cases are diagnosed
preoperatively. The remaining cases are diagnosed either after laparoscopic cholecystectomy
© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

or intraoperatively. These cases are categorized as “incidental GBC,” and their management
is more complex and challenging.
2. Incidence and prevalence
GBC is discovered incidentally during histopathology following 0.25–3.0% of laparoscopic
cholecystectomies [3–6]; however, this constitutes 74–92% of all GBC diagnoses [7, 8].
Although rare, GBC is the most common malignant disease of the biliary tract [9]. Its inci-
dence varies greatly by geographical location, ethnicity, and socioeconomic status. This varia-
tion is likely due to dierences in both environmental and genetic factors.
• Ethnicity: Unlike the vast majority of malignancies, GBC commonly occurs in South America,
in countries such as Chile, Bolivia, and Ecuador, and in Asia, in parts of India, Pakistan, Japan,
and Korea [10, 11]. Mapuche Indians in Chile exhibit the highest rate of GBC worldwide, with
rates of 12.3/100,000 and 27.3/100,000 for males and females, respectively [12]. Asia is also a
high-risk continent for GBC, with the highest incidence found in Indian women followed by
Pakistani women [11]. GBC also occurs frequently in eastern and central Europe; however, its
incidence is low in western and Mediterranean Europe, and in the United States [1].
• Age and sex: The incidence of GBC increases with age, especially in people older than 65 years
[13]. In addition, GBC incidence in women is six times that in men [3].
• Gallstone disease: Gallstones represent the most important risk factor for GBC development
[14]. However, the likelihood that an individual with gallbladder stones will develop can-
cer is as low as 0.5% [15]. The properties of the gallstones themselves play a role in the
development of GBC, as dierent types of stones induce dierent paerns of mucosal irri-
tation and chronic inammation [16]. Stones larger than 3 cm confer 10 times higher risk of
developing cancer than do smaller stones [17]. The higher prevalence of cholesterol stones
in populations with high prevalence of GBC, such as American Indians, suggests that stone
content may also be a contributing factor to cancer development [18].
• Obesity: Higher body mass index is associated with higher risk of development of gall-
stones [18]. However, data linking obesity to GBC are conicting. A recent meta-analysis
of 14 prospective cohort and 15 case control studies revealed that excess body weight is
indeed a risk factor for GBC development [19].
• Infection: Infections with certain bacteria such as Salmonella and Helicobacter spp. have been
linked to biliary malignancies [20, 21]. Chronic bacterial cholangitis also confers a strong
risk for biliary cancer.
• Other risk factors: Chronic inammatory conditions, such as primary sclerosing cholan-
gitis, have been linked to malignant transformation. Environmental exposure to factors
such as radon in mine workers [22] and tobacco [23] has also been implicated as a risk
factor for GBC. Anatomical risk factors include an anomalous pancreaticobiliary duct
junction, which is found in approximately 10% of patients with GBC [24]. Histologically,
Updates in Gallbladder Diseases80

GBC in such patients is of the papillary subtype [11], which is less invasive, with low
metastatic potential; however, a prophylactic cholecystectomy should be considered in
such patients.
The survival of these patients is largely aected by disease stage and surgical management. The
7th American Joint Commiee on Cancer (AJCC) [25] reported that the ve-year survival rate
for patients with stage 0 (Tis) GBC is estimated to be 85%, and that it drops to 50% for patients
with stage I (T1) GBC. The ve-year survival rate for patients with stage II GBC is 25%, improv-
ing to 35% after extended cholecystectomy, and for patients with stage III GBC, it is 10%. In
contrast, the survival rate of patients with stage IV GBC is extremely low, estimated to be less
than 4%.
3. Time of identication and resection
GBC can be detected during a cholecystectomy procedure if a suspicious mass is found,
or after surgery. Most these cases are diagnosed following a laparoscopic cholecystectomy
for associated symptomatic gallbladder stones. This alone is a risk factor for reexploration
to detect the presence of potential residual disease, which greatly alters the course of dis-
ease management. For gallbladder masses found during cholecystectomy, a specialized
hepatobiliary surgeon must be consulted for proper management. If no specialized sur-
geon is available, cholecystectomy should be aborted, and the patient should be referred
to a specialized center [26]. That being said, most cases of GBC are found postoperatively
on pathological examinations. These cases require further staging workup and possible
reresection depending on the disease stage. The timing of resection was not studied until
recently. A multicenter retrospective cohort study that included 207 patients specically
examined the timing of reresection surgery and its eect on the patients’ overall survival
outcomes [27]. Patients who underwent reexploration and resection were divided into
three groups on the basis of the time interval from the initial cholecystectomy to reopera-
tion: group A (less than 4 weeks), group B (4–8 weeks), and group C (more than 8 weeks).
Their ndings revealed that patients who were reoperated within 4–8 weeks (group B) had
the longest median overall survival (40 months) compared to that in groups A and C (17.2
and 22.4, respectively), despite having similar characteristics and tumor staging as these
groups.
4. Staging of incidental GBC
The principles of oncological surgery remain constant in incidental GBC. The most pivotal
and important step is accurate patient staging. Thus, a staging workup needs to be performed
for each patient. GBC stage directly aects disease management and prognosis. TNM staging,
which is recommended by AJCC guidelines [25], is the most commonly used staging system
(Table 1). Staging dictates disease management and treatment options, and predicts survival.
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• Imaging: Transabdominal ultrasound (US) is commonly the rst imaging modality used for
evaluating most gallbladder diseases; however, its resolution is insucient for GBC staging.
Endoscopic US (EUS) is a method that provides high-resolution images, and consequently,
accurate staging [28]. Unfortunately, EUS is an invasive procedure that carries the risk of
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor invades lamina propria or muscular layer
T1a Tumor invades lamina propria
T1b Tumor invades muscular layer
T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver
T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver
and/or one other adjacent organ or structure, such as the stomach, duodenum, colon,
pancreas, omentum, or extrahepatic bile ducts
T4 Tumor invades main portal vein or hepatic artery or invades 2 or more extrahepatic
organs or structures
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or
portal vein
N2 Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery
lymph nodes
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Stage T N M
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
IIIA T3 N0 M0
IIIB T1-3 N1 M0
IVA T4 N0-1 M0
IVB Any T N2 M0
Any T Any N M1
Source: From Ref. [68].
Table 1. TNM staging for gall bladder cancer.
Updates in Gallbladder Diseases82

bleeding and bowel perforation, in addition to being uncomfortable for the patient. High-
resolution US (HRUS) combines the convenience of transabdominal US with the high reso-
lution and accuracy of EUS for GBC staging [29].
The initial imaging modality for evaluating surgical resectability and providing appropri-
ate disease staging is generally a high-resolution contrast-enhanced sectional image with
a computerized tomography (CT) scan of the chest, abdomen, and pelvis. It detects the
extent of the tumor, distant metastasis, and gross lymph node involvement [30]. Although
HRUS provides higher accuracy than CT does when predicting the depth of local tumor
invasion [31], HRUS cannot replace the standard role of CT mainly because GBC resectabil-
ity is determined not just by the tumor itself, but also by its extension into adjacent organs,
vascular invasion, degree of bile duct obstruction, and the existence of metastasis [32]. CT
has the added advantage of enabling evaluation of these entities, which makes it the most
accurate modality for determining GBC resectability [33].
Local extension of disease can be evaluated further by magnetic resonance imaging (MRI),
which provides detailed evaluation of the liver parenchyma and common hepatic duct/
common bile duct, especially in patients with concomitant liver steatosis or cirrhosis.
Lymph node status can also be dicult to establish preoperatively; however, abdominal
CT and MRI increase the detection rate by up to 24% [34]. In terms of detecting metastatic
lymph nodes in general, diuse weighted MRI is more benecial than multislice CT [35].
MR cholangiopancreatography using heavily T2-weighted sequences also enables the dif-
ferentiation of the dilated bile duct from the adjacent tissues by producing bright signals
from the uid within the ducts [36].
In addition to these methods, 18-uorodeoxyglucose positron emission (FDG-PET) is a
technique that utilizes the hypermetabolic condition of malignant masses. It is combined
with CT to produce a whole body metabolic map of glucose uptake. A previous study
reported that (FDG-PET)-CT has a sensitivity of 56% for detecting omental, peritoneal, or
lymphatic spread of GBC [2]. A general drawback of FDG-PET is the possibility of a false-
positive result due to detection of inammatory areas instead of a tumor, because they both
have high glucose uptakes.
• Diagnostic laparoscopy: The use of diagnostic laparoscopy is mainly justied by the large
percentage of cases that are found to have residual nonresectable disease, in the form of
peritoneal disease, occult metastasis (not evident on imaging), or local invasion to the vas-
cular structures, which render tumors unresectable. Although the relationship between the
T stage of GBC and the benet of diagnostic laparoscopy is not yet established in cholan-
giocarcinomas [37], most researchers suggest the use of diagnostic laparoscopy in patients
with T2/3 lesions scheduled for reresection [38, 39], in order to save them the burden of a
full laparotomy. A recent meta-analysis found the accuracy of diagnostic laparoscopy to be
63.9% [40]. The sensitivity of diagnostic laparoscopy in GBC was 0.642 (95% CI: 0.579–0.7).
The use of intraoperative ultrasound increased the overall performance and contributed
to a minor increase in the overall sensitivity. Diagnostic laparoscopy prevented unneces-
sary laparotomy in 27.6% of these cases, with a mortality rate of 0.09% and morbidity of
0.37%. These data indicate that staging laparoscopy prior to laparotomy, which can be
performed within the same seing, is the recommended procedure for all GBC cases [41].
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5. Contraindications for curative surgery
Because of the fatality of GBC and its poor prognosis, aempts of curative surgery are limited
to localized resectable disease. Absolute contraindications to surgery include the presence
of distant metastasis, liver metastasis, peritoneal disease, malignant ascites, and evidence of
extensive nodal disease (para-aortic lymph nodes). Major vessel involvement, which is an
indicator of stage IV disease, is another contraindication for curative surgery [42].
In contrast, T3 disease with direct involvement of the duodenum, colon, or liver does not
preclude resectability if R0 en-bloc resection can be achieved safely [41]. It is not considered a
contraindication even though it is an indicator of aggressive disease and carries the increased
possibility of lymph node involvement, which results in poor survival outcomes.
Palliative options, if appropriate, might be the only justication for intervention in unre-
sectable cases. For example, a cholecystectomy can be performed for an acutely inamed
gallbladder, or left cholodochojejunostomy for drainage in case of failure of endoscopic
stenting.
6. Surgical management
Surgery is the mainstay of GBC treatment and the only curative option [43]. Surgical options
are dependent on the pathological staging and may involve one or more of the adjacent
organs (Figure 1).
For stage 0-I (T1, N0, and M0):
• Simple cholecystectomy
– Simple cholecystectomy might be the only treatment needed in early GBC (i.e., Tis, T1a),
as the risk of lymph node dissemination is low. However, great care should be exercised
during the handling and mobilization of the gallbladder in order to prevent bile spillage.
This is important because the bile in the gallbladder of a patient with GBC is highly con-
taminated with malignant cells, which increases the risk of dissemination of the cancer
cells to the local areas and peritoneal cavity [44]. This concern makes open cholecystec-
tomy the standard of care if the surgeon cannot guarantee an adequate resection with no
spillage during laparoscopy [41].
– The cystic duct resection margin is the main deterrent for further surgical intervention
in T1a GBC. Tumor cell involvement of the cystic duct margin justies reoperation
and resection of the extrahepatic bile duct [43, 45]. Hepatic duct involvement sug-
gests poor biology and is frequently associated with lymph node involvement [46].
If the margin is negative for cancer cells, cholecystectomy is sucient and no further
procedure is needed because further resection does not provide any survival benets
to these patients [47, 48].
Updates in Gallbladder Diseases84

• Extended cholecystectomy and lymphadenectomy
– The treatment strategy for incidental T1b GBC was controversial until recently. Extend-
ed cholecystectomy and lymphadenectomy improve cancer-specic survival and are
recommended over cholecystectomy alone [41, 49] mainly because of the high risk of
Figure 1. Schematic representation of the hilar structures including the lymph nodes groups targeted during extended
cholecystectomy.
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lymph node metastasis (11.5%) in GBC T1b. The recurrence rate after simple cholecystec-
tomy is higher than that after extended cholecystectomy (12.5 vs. 2%, respectively) [41,
50]. However, this survival benet has been debated in the literature, and simple chole-
cystectomy is considered sucient for GBC T1b, especially in eastern countries [51]. Bile
duct resection is indicated in cases with a positive cystic duct margin, since recurrence
occurs in 50% of these cases. However, there is no evidence to support routine bile duct
resection in cases with a negative cystic duct margin.
For stage II (T2, N0, and M0), stage III (T3, N0-1, and M0):
• Extended cholecystectomy and lymphadenectomy
– If no contraindication for curative surgery exists, extended cholecystectomy and lymph-
adenectomy are indicated in all cases where the GBC lesions invade the subserosal or
deeper layers (T1b, T2, and T3). This recommendation is based on the high rate of vascu-
lar and perineural invasion and lymph node metastasis in these stages. An appropriate
treatment would be extended cholecystectomy as follows:
(a) Bile duct resection
Although there is no evidence to support routine resection, it is indicated when
invasion of the cystic duct margin is evident grossly or on a frozen section.
Another indication is hepatoduodenal ligament invasion (GB neck tumor) as part
of en bloc oncologic resection [43, 45, 51]. In these cases, complete removal of the
bile duct is necessary, with further reconstruction using a Roux-en-Y hepaticoje-
junostomy technique.
(b) Extended cholecystectomy includes resection of the gallbladder bed and hepatec-
tomy to achieve an R0 oncologic resection; a 2–3-cm margin is commonly used. Liver
resection for GBC treatment ranges from partial hepatectomies (nonanatomical or
anatomical resection of segments 4a and 5) to major extended hepatectomies. Ana-
tomical resection of segments 4a and 5 is considered a good oncologic option for GBC
because the cystic vein was found to drain into segment 4a (37–90%) and segment
5 (52–90%) [52, 53]. A more aggressive approach consisting of routine right extended
hepatectomy that includes the caudate lobe has been proposed. However, major
resection does not improve survival over nonanatomical liver resection and only
increases the risk of postoperative complications [54, 55]. Furthermore, major hepa-
tectomies are associated with higher morbidity rates than partial hepatectomies are,
with no added survival benet [56–58]. Therefore, achieving R0 with limited liver
resection and fewer complications is the recommended procedure for GBC [26, 41].
(c) Major hepatectomies are indicated in select cases, which are encountered less fre-
quently in incidental GBC treatment. These are cases in which an R0 resection
cannot be achieved with partial hepatectomy or if the tumor is invading the main
blood supply of the liver lobe [59].
(d) Lymphadenectomy (Figure 1):
Lymphatic drainage of GB follows a route starting from around the cystic duct
via the portal vein/hepatic artery, into the retropancreatic and celiac/superior
Updates in Gallbladder Diseases86

mesenteric artery, and then into the para aortic area [60]. Skip lesions have also
been reported, where the tumor invades celiac lymph nodes directly without
hepatoduodenal lymph node involvement [61]. Regional lymph nodes of the gall-
bladder are dened as the nodes in the hepatoduodenal ligament, the nodes along
the common hepatic artery, and the nodes cranial to the duodenal papilla on the
posterior surface of the head of the pancreas [62]. Therefore, lymphadenectomy
of GBC should include at least regional lymph nodes of the gallbladder [26, 41].
According to AJCC guidelines, a minimum of three lymph nodes are required
for accurate nodal status evaluation, although recent studies have shown that a
minimum of six lymph nodes are needed for accurate nodal evaluation [63, 64].
It is debatable whether extended lymphadenectomy (including celiac/superior
mesenteric artery lymph node) as a part of routine lymph node dissection in GBC
confers a survival benet. However, studies suggest that extended lymphadenec-
tomy ensures the removal of an adequate number of lymph nodes (more than six)
and the removal of skipped lymph nodes for proper nodal staging. Therefore,
extended lymphadenectomy is routinely practiced in high-volume centers [54, 61].
• Port site resections:
– Port site resection has been proposed for lowering the chances of cancer recurrence at
the site of a previous cholecystectomy. However, the use of this procedure is not sup-
ported by the evidence found in the scientic literature [41]. Port site resection does not
seem to improve survival and carries a 15% risk of incisional hernia. Patients with docu-
mented port site metastasis after resection develop peritoneal disease soon after [57, 65].
Therefore, routine port site resection is not recommended [41].
For stage IV and unresectable disease:
– Patients with locally advanced GBC and unresectable disease are considered beyond the
scope of curative treatment. Patients with preoperatively determined locally advanced
disease (T3-4, N2) should be enrolled in clinical trials assessing neoadjuvant treatment.
If these patients undergo resection, they should be enrolled in clinical trials assessing
adjuvant treatment [41]. The main treatment is palliative, with the aim of ameliorating
the patient’s symptoms. Biliary obstruction, pain, cachexia, and infections are the usual
targets for such palliative treatment. A single- or double-agent chemotherapy regimen
can be added according to patient tolerance and performance status in order to provide
palliation and prolong survival [26, 41].
7. Importance of postoperative pathological evaluation following
laparoscopic cholecystectomy
The classical postsurgical approach is to review every tissue histopathologically in order to
document any concerns regarding the diagnosis and to exclude any oncological etiology. The
microscopic examination of at least three sections is recommended, especially in high inci-
dence areas [41]. The increase in cost and pathologists’ workload due to evaluation of specimens
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from the most commonly performed surgery worldwide remains debatable. Yet, this practice
might result in diagnosis of GBC in 0.25–3.0% of all samples evaluated [3–6]. Some studies

the perioperative period, on radiological imaging, and on macroscopic examination of the
gallbladder. Thickening of the gallbladder wall and mucosal ulceration are the most common
signs associated with malignancy [66, 67]. However, the evidence to support such a practice
is still lacking.
8. Conclusion
GBC is a rare but fatal disease. Most cases are discovered incidentally while treating a benign
disease, indicating the importance of histopathological exam after all cholecystectomies.
Therapy can be multimodal yet surgical intervention is the mainstay of GBC treatment. The
most pivotal and important step is accurate preoperative staging. Staging dictates disease
management and treatment options and can predict survival. Due to the rarity of the disease
patients should be recruited to ongoing multicentral clinical trials.
Author details
         


1 Department of Surgery, King Saud University, Riyadh, Saudi Arabia
2 Department of Oncology, McGill University Health Center, Montreal, Canada
References
[1] Levy AD, Murakata LA, Rohrmann CA, Jr. Gallbladder carcinoma: radiologic-patho-
logic correlation. Radiographics. 2001;21(2):295–314; questionnaire, 549–55.
[2]         
Ramia-Angel JM, et al. Application of modern imaging methods in diagnosis of gall-
bladder cancer. J Surg Oncol. 2006;93(8):650–64.
[3]    
KK, et al. Trends in presentation and survival for gallbladder cancer during a period of more
than 4 decades: a single-institution experience. Arch Surg. 2009;144(5):441–7; discussion 7.
[4] 
carcinoma in the era of laparoscopic cholecystectomy. Arch Surg. 1996;131(9):981–4; dis-
cussion 5.
Updates in Gallbladder Diseases88

[5] Duy A, Capanu M, Abou-Alfa GK, Huiil D, Jarnagin W, Fong Y, et al. Gallbladder
cancer (GBC): 10-year experience at Memorial Sloan-Keering Cancer Centre (MSKCC).
J Surg Oncol. 2008;98(7):485–9.
[6] Miller G, Jarnagin WR. Gallbladder carcinoma. Eur J Surg Oncol. 2008;34(3):306–12.
[7] Yamamoto H, Hayakawa N, Kitagawa Y, Katohno Y, Sasaya T, Takara D, et al.
Unsuspected gallbladder carcinoma after laparoscopic cholecystectomy. J Hepatobiliary
Pancreat Surg. 2005;12(5):391–8.
[8] Tantia O, Jain M, Khanna S, Sen B. Incidental carcinoma gall bladder during laparoscopic
cholecystectomy for symptomatic gall stone disease. Surg Endosc. 2009;23(9):2041–6.
[9] Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba, II, et al.
Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin.
2001;51(6):349–64.
[10] Strom BL, Soloway RD, Rios-Dalenz JL, Rodriguez-Martinez HA, West SL, Kinman JL, et
al. Risk factors for gallbladder cancer. An international collaborative case–control study.
Cancer. 1995;76(10):1747–56.
[11] Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distri-
bution and risk factors. Int J Cancer. 2006;118(7):1591–602.
[12] Surveillance, Epidemiology End-Results Program (SEER) The Four Most Common Cancers
for Dierent Ethnic Populations 2013. Bethesda, MD: National Cancer Institute. 2013.
[13] Portincasa P, Moschea A, Petruzzelli M, Palasciano G, Di Ciaula A, Pezzolla A.
Gallstone disease: symptoms and diagnosis of gallbladder stones. Best Pract Res Clin
Gastroenterol. 2006;20(6):1017–29.
[14] Hsing AW, Gao YT, Han TQ, Rashid A, Sakoda LC, Wang BS, et al. Gallstones and
the risk of biliary tract cancer: a population-based study in China. Br J Cancer.
2007;97(11):1577–82.
[15] Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas.
Cancer. 1995;75(1 Suppl):171–90.
[16] Shaer EA. Gallbladder cancer: the basics. Gastroenterol Hepatol (N Y). 2008;4(10):737–41.
[17] Lowenfels AB, Walker AM, Althaus DP, Townsend G, Domellof L. Gallstone growth,
size, and risk of gallbladder cancer: an interracial study. Int J Epidemiol. 1989;18(1):50–4.
[18] Shaer EA. Gallstone disease: epidemiology of gallbladder stone disease. Best Pract Res
Clin Gastroenterol. 2006;20(6):981–96.
[19] Li L, Gan Y, Li W, Wu C, Lu Z. Overweight, obesity and the risk of gallbladder and
extrahepatic bile duct cancers: A meta-analysis of observational studies. Obesity (Silver
Spring). 2016;24(8):1786–802.
[20] Kumar S, Kumar S, Kumar S. Infection as a risk factor for gallbladder cancer. J Surg
Oncol. 2006;93(8):633–9.
Incidental Gallbladder Cancer
http://dx.doi.org/10.5772/67654
89

[21] Gonzalez-Escobedo G, Marshall JM, Gunn JS. Chronic and acute infection of the gall
bladder by Salmonella Typhi: understanding the carrier state. Nat Rev Microbiol.
2011;9(1):9–14.
[22] Darby SC, Whitley E, Howe GR, Hutchings SJ, Kusiak RA, Lubin JH, et al. Radon and
cancers other than lung cancer in underground miners: a collaborative analysis of 11
studies. J Natl Cancer Inst. 1995;87(5):378–84.
[23] Jain K, Sreenivas V, Velpandian T, Kapil U, Garg PK. Risk factors for gallbladder cancer:
a case–control study. Int J Cancer. 2013;132(7):1660–6.
[24] Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: recognition of risk factors and
the role of prophylactic cholecystectomy. Am J Gastroenterol. 2000;95(6):1402–10.
[25] Edge SB, Byrd DR, Compton CC, Fri AG, Greene FL, Troi A, et al. AJCC Cancer
Staging Manual (7th ed): New York, NY: Springer; 2010.
[26] Benson AB, 3rd, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, et al.
NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr
Canc Netw. 2009;7(4):350–91.
[27] Ethun CG, Postlewait LM, Le N, Pawlik TM, Buener S, Poultsides G, et al. Association
of optimal time interval to re-resection for incidental gallbladder cancer with overall
survival: a multi-institution analysis from the US extrahepatic biliary malignancy con-
sortium. JAMA Surg. 2017;152(2):143–149.
[28] Akatsu T, Aiura K, Shimazu M, Ueda M, Wakabayashi G, Tanabe M, et al. Can endo-
scopic ultrasonography dierentiate nonneoplastic from neoplastic gallbladder polyps?
Dig Dis Sci. 2006;51(2):416–21.
[29] Lee JS, Kim JH, Kim YJ, Ryu JK, Kim YT, Lee JY, et al. Diagnostic accuracy of transab-
dominal high-resolution US for staging gallbladder cancer and dierential diagnosis of
neoplastic polyps compared with EUS. Eur Radiol. 2016:1–7.
[30] Kumaran V, Gulati S, Paul B, Pande K, Sahni P, Chaopadhyay K. The role of dual-
phase helical CT in assessing resectability of carcinoma of the gallbladder. Eur Radiol.
2002;12(8):1993–9.
[31] Jang JY, Kim SW, Lee SE, Hwang DW, Kim EJ, Lee JY, et al. Dierential diagnostic and
staging accuracies of high resolution ultrasonography, endoscopic ultrasonography,
and multidetector computed tomography for gallbladder polypoid lesions and gallblad-
der cancer. Ann Surg. 2009;250(6):943–9.
[32] Pilgrim CH, Usato V, Evans P. Consideration of anatomical structures relevant to the sur-
gical strategy for managing gallbladder carcinoma. Eur J Surg Oncol. 2009;35(11):1131–6.
[33] Li B, Xu XX, Du Y, Yang HF, Li Y, Zhang Q, et al. Computed tomography for assess-
ing resectability of gallbladder carcinoma: a systematic review and meta-analysis. Clin
Imaging. 2013;37(2):327–33.
Updates in Gallbladder Diseases90

[34] Kokudo N, Makuuchi M, Natori T, Sakamoto Y, Yamamoto J, Seki M, et al. Strategies for
surgical treatment of gallbladder carcinoma based on information available before resec-
tion. Arch Surg. 2003;138(7):741–50; discussion 50.
[35] Morine Y, Shimada M, Imura S, Ikemoto T, Hanaoka J, Kanamoto M, et al. Detection of
lymph nodes metastasis in biliary carcinomas: morphological criteria by MDCT and the
clinical impact of DWI-MRI. Hepatogastroenterology. 2015;62(140):777–81.
[36] Jung SJ, Woo SM, Park HK, Lee WJ, Han MA, Han SS, et al. Paerns of initial disease
recurrence after resection of biliary tract cancer. Oncology. 2012;83(2):83–90.
[37] Connor S, Barron E, Wigmore SJ, Madhavan KK, Parks RW, Garden OJ. The utility of
laparoscopic assessment in the preoperative staging of suspected hilar cholangiocarci-
noma. J Gastrointest Surg. 2005;9(4):476–80.
[38] Tilleman EH, de Castro SM, Busch OR, Bemelman WA, van Gulik TM, Obertop H, et al.
Diagnostic laparoscopy and laparoscopic ultrasound for staging of patients with malig-
nant proximal bile duct obstruction. J Gastrointest Surg. 2002;6(3):426–30; discussion 30–1.
[39] Weber SM, DeMaeo RP, Fong Y, Blumgart LH, Jarnagin WR. Staging laparoscopy
in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg.
2002;235(3):392–9.
[40] Tian Y, Liu L, Yeolkar NV, Shen F, Li J, He Z. Diagnostic role of staging laparoscopy in a
subset of biliary cancers: a meta-analysis. ANZ J Surg. 2016;87(1-2):22–27.
[41] Aloia TA, Jarufe N, Javle M, Maithel SK, Roa JC, Adsay V, et al. Gallbladder cancer:
expert consensus statement. HPB (Oxford). 2015;17(8):681–90.
[42] Yoshitomi H, Miyakawa S, Nagino M, Takada T, Miyazaki M. Updated clinical prac-
tice guidelines for the management of biliary tract cancers: revision concepts and major
revised points. J Hepatobiliary Pancreat Sci. 2015;22(4):274–8.
[43] Jayaraman S, Jarnagin WR. Management of gallbladder cancer. Gastroenterol Clin North
Am. 2010;39(2):331–42.
[44] Lee JM, Kim BW, Kim WH, Wang HJ, Kim MW. Clinical implication of bile spillage
in patients undergoing laparoscopic cholecystectomy for gallbladder cancer. Am Surg.
2011;77(6):697–701.
[45] Pawlik TM, Gleisner AL, Vigano L, Kooby DA, Bauer TW, Frilling A, et al. Incidence of
nding residual disease for incidental gallbladder carcinoma: implications for re-resec-
tion. J Gastrointest Surg. 2007;11(11):1478–86; discussion 86–7.
[46] Birnbaum DJ, Vigano L, Ferrero A, Langella S, Russolillo N, Capussoi L. Locally
advanced gallbladder cancer: which patients benet from resection? Eur J Surg Oncol.
2014;40(8):1008–15.
[47] Ouchi K, Mikuni J, Kakugawa Y, Organizing Commiee TtACotJSoBS. Laparoscopic
cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients.
J Hepatobiliary Pancreat Surg. 2002;9(2):256–60.
Incidental Gallbladder Cancer
http://dx.doi.org/10.5772/67654
91

[48] Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladder cancer: a population-
based analysis. J Am Coll Surg. 2008;207(3):371–82.
[49] Hari DM, Howard JH, Leung AM, Chui CG, Sim MS, Bilchik AJ. A 21-year analysis
of stage I gallbladder carcinoma: is cholecystectomy alone adequate? HPB (Oxford).
2013;15(1):40–8.
[50] Lee SE, Jang JY, Lim CS, Kang MJ, Kim SW. Systematic review on the surgical treatment
for T1 gallbladder cancer. World J Gastroenterol. 2011;17(2):174–80.
[51] Miyazaki M, Yoshitomi H, Miyakawa S, Uesaka K, Unno M, Endo I, et al. Clinical prac-
tice guidelines for the management of biliary tract cancers 2015: the 2nd English edition.
J Hepatobiliary Pancreat Sci. 2015;22(4):249–73.
[52] Yoshimitsu K, Honda H, Kaneko K, Kuroiwa T, Irie H, Chijiiwa K, et al. Anatomy
and clinical importance of cholecystic venous drainage: helical CT observations dur-
ing injection of contrast medium into the cholecystic artery. AJR Am J Roentgenol.
1997;169(2):505–10.
[53] Suzuki M, Yamamoto K, Unno M, Katayose Y, Endo K, Oikawa M, et al. Detection of per-
fusion areas of the gallbladder vein on computed tomography during arterial portogra-
phy (CTAP)—the background for dual S4a.S5 hepatic subsegmentectomy in advanced
gallbladder carcinoma. Hepatogastroenterology. 2000;47(33):631–5.
[54] Shirai Y, Wakai T, Sakata J, Hatakeyama K. Regional lymphadenectomy for gallbladder
cancer: rational extent, technical details, and patient outcomes. World J Gastroenterol.
2012;18(22):2775–83.
[55] Horiguchi A, Miyakawa S, Ishihara S, Miyazaki M, Ohtsuka M, Shimizu H, et al.
Gallbladder bed resection or hepatectomy of segments 4a and 5 for pT2 gallbladder
carcinoma: analysis of Japanese registration cases by the study group for biliary surgery
of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat
Sci. 2013;20(5):518–24.
[56] Bue JM, Waugh E, Meneses M, Parada H, De La Fuente HA. Incidental gallbladder
cancer: analysis of surgical ndings and survival. J Surg Oncol. 2010;102(6):620–5.
[57] Fuks D, Regimbeau JM, Le Treut YP, Bachellier P, Raventos A, Pruvot FR, et al. Incidental
gallbladder cancer by the AFC-GBC-2009 Study Group. World J Surg. 2011;35(8):1887–97.
[58] D’Angelica M, Dalal KM, DeMaeo RP, Fong Y, Blumgart LH, Jarnagin WR. Analysis
of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol.
2009;16(4):806–16.
[59] Endo I, Shimada H, Takimoto A, Fujii Y, Miura Y, Sugita M, et al. Microscopic liver
metastasis: prognostic factor for patients with pT2 gallbladder carcinoma. World J Surg.
2004;28(7):692–6.
[60] Shirai Y, Yoshida K, Tsukada K, Ohtani T, Muto T. Identication of the regional lym-
phatic system of the gallbladder by vital staining. Br J Surg. 1992;79(7):659–62.
Updates in Gallbladder Diseases92

[61] Birnbaum DJ, Vigano L, Russolillo N, Langella S, Ferrero A, Capussoi L. Lymph node
metastases in patients undergoing surgery for a gallbladder cancer. Extension of the
lymph node dissection and prognostic value of the lymph node ratio. Ann Surg Oncol.
2015;22(3):811–8.
[62] Miyazaki M, Ohtsuka M, Miyakawa S, Nagino M, Yamamoto M, Kokudo N, et al.
Classication of biliary tract cancers established by the Japanese Society of Hepato-
Biliary-Pancreatic Surgery: 3(rd) English edition. J Hepatobiliary Pancreat Sci.
2015;22(3):181–96.
[63] Ito H, Ito K, D’Angelica M, Gonen M, Klimstra D, Allen P, et al. Accurate staging for
gallbladder cancer: implications for surgical therapy and pathological assessment. Ann
Surg. 2011;254(2):320–5.
[64] Negi SS, Singh A, Chaudhary A. Lymph nodal involvement as prognostic factor in gall-
bladder cancer: location, count or ratio? J Gastrointest Surg. 2011;15(6):1017–25.
[65] Maker AV, Bue JM, Oxenberg J, Kuk D, Gonen M, Fong Y, et al. Is port site resec-
tion necessary in the surgical management of gallbladder cancer? Ann Surg Oncol.
2012;19(2):409–17.
[66] Wrenn SM, Callas PW, Abu-Jaish W. Histopathological examination of specimen fol-
lowing cholecystectomy: are we accepting resect and discard? Surg Endosc. 2017;31(2):
586–593.
[67] Talreja V, Ali A, Khawaja R, Rani K, Samnani SS, Farid FN. Surgically resected gall blad-
der: is histopathology needed for all? Surg Res Pract. 2016;2016:9319147.
[68] Edge SB, Compton CC. The American Joint Commiee on Cancer: the 7th edition of the
AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.
Incidental Gallbladder Cancer
http://dx.doi.org/10.5772/67654
93