98

THE GALLBLADDER
STEVEN A. CURLEY, MD, FACS

Adenocarcinoma of the gallbladder is the sixth most common

digestive-system malignancy in the United States. When compared
with the worldwide incidence of hepatocellular carcinoma (HCC),
gallbladder carcinoma accounts for less than 10% of the annual cases
of primary hepatobiliary cancer. However, in western countries such
as the United States where there is a low incidence of HCC, gallbladder cancer is relatively more prevalent with an estimated 7,200 cases
of gallbladder and extrahepatic bile duct cancer diagnosed in 1999
compared with 14,500 cases of HCC and intrahepatic bile duct cancer
in the same year.1 Autopsy and biliary tract operation data from
112,713 patients revealed an average incidence of gallbladder carcinoma ranging from 0.55 to 1.91%.2 Over the past three decades, there
appears to be a slight increase in the incidence of gallbladder carcinoma in western countries, but this may be ascribed to more thorough
reporting mechanisms rather than to a true increase in incidence.2
Gallbladder carcinoma is a disease that is diagnosed most frequently
in the sixth and seventh decades of life. Unlike HCC and cholangiocarcinoma, gallbladder carcinoma has a higher incidence in females
than males, with a ratio of approximately 3:1.2 The preponderance of
this cancer in females is even greater in patients less than 40 years old,
with a female-to-male ratio of 20:1.3
Gallbladder carcinoma is more prevalent in Southwest American
Indians. The incidence of this disease is six times higher than that in
non-Indian populations, and gallbladder carcinoma has been found in
6% of Southwest American Indians undergoing biliary tract surgery.4
Gallbladder carcinoma is the second most common gastrointestinal
malignancy in this population, and the youngest reported case of gallbladder carcinoma occurred in an 11-year-old Navajo girl.5
Other human populations also have an increased incidence of gallbladder cancer. In Chile, the incidence of gallbladder cancer is rising,
and gallbladder cancer is the number one cause of cancer mortality in
Chilean women.6 The geographic and population-based variations in
the incidence of gallbladder cancer suggests that environmental risk
factors, including carcinogens, infectious agents like Salmonella typhi
and Helicobacter pylori, and diet are likely to have a role in gallbladder tumorigenesis.
CAUSATIVE FACTORS There are no apparent associations between
gallbladder carcinoma and hepatitis B or C virus infection, cirrhosis,
or mycotoxin exposure. Similarly, chemical hepatocarcinogens have
not been clearly demonstrated to increase the risk of developing gallbladder carcinoma. However, there are suggestions that workers
exposed to carcinogenic substances, such as methylcholanthrene and
nitrosamines, have a higher incidence and earlier onset of gallbladder
carcinoma when compared with control populations.7 Experimental
studies indicate that animals exposed to hepatocarcinogens alone
rarely form gallbladder carcinoma, but when the animals are also fed
a gallstone-inducing diet, over 50% developed gallbladder carcinoma.8 There is a significant association between gallstones and gallbladder carcinoma, with gallstones present in 74 to 92% of patients
with gallbladder carcinoma.911 The risk of developing gallbladder
carcinoma increases directly with increasing gallstone size.12 Patients
with gallstones 2.0 to 2.9 cm in diameter have a 2.4 times higher relative risk to develop gallbladder carcinoma, whereas patients with gallstones greater than 3.0 cm in diameter have a 10.1 times higher risk of
developing gallbladder carcinoma. Patients with longstanding chronic
cholecystitis can develop calcification of the gallbladder wall, also
known as porcelain gallbladder. It is possible that chronic inflammation and/or infection of the gallbladder increases the risk of developing gallbladder carcinoma because 22% of patients with calcified gallbladders have gallbladder carcinoma.13,14 Furthermore, pathogenic
bacteria are cultured from the gallbladders of patients with gallbladder
cancer at a significantly greater frequency than from patients with
simple cholelithiasis.15 Cholelithiasis and cholecystitis are more com-

mon in females, which may in part explain the higher incidence of

gallbladder carcinoma in females.16
Gallstones or other factors that cause chronic inflammation of the
gallbladder mucosa may induce a series of premalignant changes. If
not treated with a cholecystectomy, patients with these premalignant
lesions may progress to invasive gallbladder carcinoma. Epithelial
dysplasia, atypical hyperplasia, and carcinoma in situ have been identified in the gallbladder mucosa of 83, 13.5, and 3.5%, respectively, of
patients undergoing cholecystectomy for cholelithiasis or cholecystitis.17 Areas of mucosal dysplasia can be observed in over 90% of
patients with invasive gallbladder carcinoma.18 There also is evidence
that adenomatous polyps arising from the gallbladder mucosa are premalignant lesions because a review of 1,605 cholecystectomies produced 11 benign adenomas, 7 adenomas with areas of malignant transformation, and 79 invasive gallbladder carcinomas.19 Regions of
residual adenomas were found in 20% of the cases of invasive gallbladder carcinoma. There appears to be an increased expression of
epithelial growth factors and protooncogenes, particularly ras, in the
progression from chronic cholecystitis to dysplasia and then to invasive carcinoma.20 In patients with anomalous pancreaticobiliary ductal union, a condition known to be associated with an increased risk of
developing gallbladder cancer, chronic inflammation results in hyperplasia of the gallbladder epithelium.21 K-ras mutations were noted in
some of these patients with high-grade hyperplasia, suggesting that
mutations in this proto-oncogene may be an early event in gallbladder
mucosal proliferation leading to carcinogenesis. Studies performed in
patients with frank gallbladder carcinoma have demonstrated that the
majority have abnormal or mutated tumor suppressor (p53), cell cycle
regulation (cyclin E), and apoptosis regulation (Bc1-2) genes.22,23
PATHOLOGY The gross appearance of gallbladder carcinoma varies,
depending on the stage of the disease and extent of spread. Early stage
lesions that have not infiltrated through all layers of the gallbladder wall
may be indistinguishable from chronic cholecystitis. On opening the
gallbladder in these early-stage patients, gallstones usually are present,
and there may be subtle mucosal abnormalities, such as plaque-like
lesions or small ulcerations. Occasionally, a sessile or pedunculated
tumor is present and suggests the diagnosis of a gallbladder carcinoma.24 More advanced gallbladder carcinomas are grossly evident by
infiltration into the liver or contiguous organs, such as the duodenum or
stomach.25 These tumors are white to gray on cut section and very firm.
When associated with a calcified gallbladder, these carcinomas are
extremely hard, difficult to section, and have a gritty consistency.
Microscopically, over 90% of gallbladder carcinomas are adenocarcinomas, with the remaining cases being adenosquamous carcinomas, anaplastic carcinomas, and rarely carcinoid tumors or embryonal
rhabdomyosarcoma.9,24 Carcinoma in situ is an early lesion, with the
malignant cellular characteristics involving only the mucosal layer of
the gallbladder wall. Gallbladder adenocarcinomas generally have a
predominant papillary or tubular arrangement of cells.24 Papillary adenocarcinoma is characterized by an extended stroma covered by columnar cells. The tubular formations of tubular adenocarcinoma may be
lined by tall columnar cells or by cuboidal epithelium. Mucin production and signet-ring cells can be identified frequently in gallbladder
adenocarcinomas.24 More poorly differentiated carcinomas have solid
sheets or nests of small, scattered cells infiltrating into the stroma and
destroying the normal gallbladder wall architecture. The hallmark of
each of these types of invasive carcinoma is infiltration into the muscle
and adventitial layers of the gallbladder wall. Vascular, lymphatic, and
perineural invasion by the carcinoma can be demonstrated frequently.
Advanced loco-regional disease usually is present at the time of
diagnosis of gallbladder carcinoma. Only 10% of patients with this
disease have cancer confined to the gallbladder wall.9 Direct extension
of the carcinoma into the gallbladder fossa of the liver is present in 69
to 83% of patients.2527 Direct invasion of the liver usually indicates
the presence of other regional disease because less than 12% of
patients with liver involvement have no other sites of regional disease.
Direct invasion of the extrahepatic biliary tract occurs in 57% of cases;
the duodenum, stomach, or transverse colon are involved in 40%; and

1416 SECTION 29 / Neoplasms of the Alimentary Canal

the pancreas is involved in 23%.2 The hepatic artery or portal vein is

encased by tumor in 15% of patients. Regional lymph node metastases
in the cystic, choledochal, or pancreaticoduodenal lymphatic drainage
basins are present in 42 to 70% of patients.25 Somewhat more distant
lymph node metastases occur along the aorta or inferior vena cava in
approximately 25% of cases. Importantly, lymph node metastases can
occur in the absence of liver or other contiguous organ involvement by
the gallbladder carcinoma.
The pattern of lymph node metastases from gallbladder carcinoma
is predictable on the basis of anatomic studies that have identified three
pathways of lymphatic drainage of the gallbladder28 (Fig. 98.1). The
main pathway is the cholecysto-retropancreatic pathway, with lymphatic vessels on the anterior and posterior surface of the gallbladder
that converge at a large retroportal lymph node. This principal retroportal lymph node communicates with the choledochal and pancreaticoduodenal lymph nodes. The cholecysto-celiac pathway consists of
lymphatics from the anterior and posterior walls of the gallbladder that
run to the left in front of the portal vein and then communicate with
groups of pancreaticoduodenal lymph nodes or aortico-caval lymph
nodes lying near the left renal vein. The final pattern of spread of gallbladder carcinoma is related to vascular invasion. Noncontiguous liver,
pulmonary, and bone metastases have been found in 66, 24, and 12%
of gallbladder carcinoma patients, respectively.25
The staging systems used for gallbladder carcinoma are based on the
pathologic characteristics of local invasion by the tumor and lymph node
metastases. Before the American Joint Cancer Committee (AJCC) developed a tumor-node-metastasis (TNM) staging schema for gallbladder
carcinoma, the Nevin staging system was used frequently.29 Studies of
gallbladder carcinoma performed in Japan generally apply the staging
system of the Japanese Society of Biliary Surgery.30 Most recent studies
stage patients according to the TNM criteria. Carcinoma in situ corresponds to a T1aN0M0 tumor in the AJCC staging system. The characteristics of these three staging systems are outlined in Table 98.1.
CLINICAL PRESENTATION The most common symptoms and signs in
patients with gallbladder carcinoma are nonspecific. Right upper

Figure 98.1. Patterns of lymphatic drainage from the gallbladder. A, The

main pathway of lymphatic drainage and, thus, lymph node metastasis
from gallbladder cancer, is to the cholecysto-retropancreatic nodes. This
pathway drains from the gallbladder to nodes along the cystic duct and
common bile duct and then to nodes posterior to the duodenum and pancreatic head. B, The cholecysto-celiac pathway courses from the gallbladder through the gastrohepatic ligament to celiac nodes. C, The third lymphatic drainage route is the cholecysto-mesenteric pathway, coursing from
the gallbladder posterior to the pancreas to aortocaval lymph nodes.

Table 98.1. Comparison of the Three Most Commonly Used Staging

Systems for Gallbladder Carcinoma
Stage

I
II

Nevin

Cancer confined to
the mucosa
Cancer involves the
mucosa and muscularis

III

Cancer extends through

the serosa (all three layers
of the gallbladder wall
involved)

IV

Tumor through all three

layers of the gallbladder
wall with cystic lymph
node metastasis
Tumor invades the liver
by direct extension
and/or metastasis
to any distant organ

JSBS

AJCC-TNM

Cancer confined to
subserosal layers
Direct invasion of the
liver and/or bile duct,
porta hepatis lymph
node metastases
More extensive liver
invasion by cancer,
more extensive
regional lymph
node metastases
(gastrohepatic,
retropancreatic)
Liver, peritoneal,
and/or distant
organ metastases

T1aN0M0
T1bN0M0
T2N0M0

No stage V

No stage V

T1N1M0
T2N1M0
T3AnyNM0

T4AnyNM0
AnyTAnyNM1

JSBS = Japanese Society of Biliary Surgery; AJCC = American Joint Cancer Commission.
T = Primary Tumor; Tx = primary tumor cannot be assessed; T1 = tumor invades mucosa
or muscle layer; T1a = tumor invades mucosa; T1b = tumor invades muscle; T2 = tumor
invades perimuscular connective tissue, no extension beyond serosa or into liver; T3 =
tumor invades beyond serosa or into one adjacent organ or both (extension < 2 cm into
liver); T4 = tumor extends > 2 cm into liver and/or into two or more adjacent organs
(stomach, duodenum, colon, pancreas, omentum, extrahepatic bile ducts). N = Regional
lymph nodes; Nx = regional lymph nodes cannot be assessed; N0 = no regional lymph node
metastasis; N1 = regional lymph node metastasis; N1a = metastasis in cystic duct, pericholedochal, and/or gastrohepatic lymph nodes; N1b = metastasis in peripancreatic, periduodenal,
periportal, celiac, and/or superior mesenteric artery lymph nodes; M = distant metastasis;
Mx = presence of distant metastasis cannot be assessed; M0 = no distant metastasis;
M1 = distant metastasis.

quadrant abdominal pain, which may or may not be exacerbated by

eating a fatty meal, is the predominant presenting complaint in 75 to
97% of patients.2,9,31 Right upper quadrant abdominal tenderness is
present in a slightly smaller percentage of patients. These symptoms
and signs usually are ascribed to cholelithiasis or cholecystitis. Nausea, vomiting, and anorexia are present in 40 to 64% of patients; clinically evident jaundice is present in 45%; and weight loss of greater
than 10% of normal body weight is noted in 37 to 77%.
Although 45% of patients obviously are jaundiced at presentation, 70% of patients present with a serum bilirubin elevated at least
two times greater than normal.31 Serum alkaline phosphatase levels
are elevated in two-thirds of patients with gallbladder carcinoma. Alanine aminotransferase and aspartate aminotransferase levels are elevated in one-third of patients and are consistent with advanced hepatic invasion and metastases. Serum carcinoembingonic antigen
(CEA) levels generally are obtained only in patients diagnosed preoperatively with advanced stages of disease. In these patients with
TNM stage III or IV disease, the serum CEA level is elevated in over
80% of patients.31 The incidence of elevated serum CEA levels in
early stage disease is not known.
DIAGNOSTIC STUDIES Before ultrasonography and CT became
widely available, the preoperative diagnosis rate for gallbladder carcinoma was only 8.6 to 16.3%.2,32 Ultrasonography is the primary imaging study for symptomatic patients with presumed cholelithiasis or
choledocholithiasis. High-resolution ultrasonography is able to detect
early and locally advanced gallbladder carcinoma.33 Early tumors as
small as 5 mm can be recognized as a polypoid mass projecting into
the gallbladder lumen or as a focal thickening of the gallbladder
wall.34,35 In patients with locally advanced gallbladder carcinoma,
ultrasonography can demonstrate extrahepatic and intrahepatic bile
duct obstruction, porta hepatis lymphadenopathy, direct hepatic exten-

sion of tumor, and hepatic metastases. Preoperative ultrasonography

may suggest the correct diagnosis in up to 75% of patients with gallbladder carcinoma.34,36,37 However, ultrasonography does not accurately detect celiac or paraortic lymphadenopathy or peritoneal dissemination of tumor.38 Bloodflow studies with color Doppler
ultrasonography are also useful because gallbladder cancers have high
velocity arterial flow in 90% of cases, while benign lesions have minimal flow.39 Recent advances in endoscopic ultrasonography, including the use of contrast-enhancing agents, may improve the diagnostic
accuracy in assessing the T stage of the gallbladder cancer.40
CT scans are performed less frequently in patients with presumed
benign biliary tract disease. However, if gallbladder carcinoma is suspected, CT findings can predict correctly the diagnosis in 88 to 95% of
patients.4144 The CT characteristics of gallbladder carcinoma include
diffuse or focal gallbladder wall thickness of greater than 0.5 mm in
95% of patients, gallbladder wall contrast enhancement in 95%, and
intraluminal mass in 90%, direct liver invasion by tumor in 85%
(Fig. 98.2), regional lymphadenopathy in 65%, concomitant cholelithiasis in 52%, dilated intrahepatic or extrahepatic bile ducts in 50%, noncontiguous liver metastases in 12%, invasion of contiguous gastrointestinal tract organs in 8%, and intraluminal galbladder gas in 4%.43 CT
also can demonstrate calcification of the gallbladder wall (Fig. 98.3).
TREATMENT Resection. The curative resection rates for gallbladder
carcinoma range from 10 to 30%.4547 The majority of patients are not
candidates for curative resection because of extensive locoregional disease, noncontiguous liver metastases, and/or distant metastases. While
it is clear that long-term survival can be achieved in some patients with
resectable lesions, the extent of resection remains a controversial issue.
A large majority of surgeons consider simple cholecystectomy to
be adequate treatment for gallbladder carcinoma confined to the
mucosa (T1aN0M0). The 5-year survival rate for patients undergoing
simple cholecystectomy for disease confined to the mucosa ranges
from 57 to 100%.4851 There is no universal agreement on simple
cholecystectomy as the sole treatment for patients with T1aN0M0
tumors; some authors recommend that extended cholecystectomy
(cholecystectomy, wedge resection of the gallbladder fossa including a
3- to 5-cm margin of normal liver, and a cystic, pericholedochal, gastrohepatic, pancreaticoduodenal, and para-aortic lymphadenectomy)
be performed to treat patients with these very early stage lesions.52,53
These authors recommend that all gallbladders be opened at the time of
cholecystectomy for frozen section evaluation of any suspicious areas
in the mucosa. If an unsuspected gallbladder carcinoma is diagnosed by
frozen section biopsy or if a T1aN0M0 gallbladder carcinoma is diagnosed on final pathology, these authors advocate that an extended
cholecystectomy be performed. The bias for this aggressive surgical
treatment of T1aN0M0 gallbladder carcinoma is based on the small
number of cases of regional lymph node recurrence in patients treated

Figure 98.2. High-resolution, helical CT scan in a patient with gallbladder

carcinoma. Direct tumor invasion into the hepatic parenchyma is evident
(arrow).

CHAPTER 98 / The Gallbladder 1417

Figure 98.3. A high-resolution, helical CT scan in another patient with

gallbladder cancer. A locally invasive tumor is again noted with areas of
calcification (arrow) noted in the thickened gallbladder wall.

with simple cholecystectomy alone. No rationale is provided for the

liver resection because the small number of patients who did fail after
simple cholecystectomy developed metastases in the pericholedochal
or cystic lymph nodes and not in the liver. Furthermore, the incidence
of subsequent lymph node metastases in T1aN0M0 patients was less
than 10% in the small groups of 32 and 36 patients, respectively.52,53
The incidence of lymph node metastases in 201 patients with gallbladder carcinoma confined to the mucosa was only 2.5% in a study of
patients who underwent cholecystectomy and regional lymphadenectomy.49 The mortality rate for extended resection ranges from 2 to 5%,
and major postoperative morbidity occurs in 13 to 40%.4850,54 Therefore, the morbidity and mortality associated with extended cholecystectomy is excessive compared with the potential survival benefit that
would occur in less than 5% of patients with T1aN0M0 lesions.
There is a rationale for performing extended cholecystectomy in
patients with T1b tumors or AJCC TNM stage II and III gallbladder
carcinomas (Fig. 98.4). In 165 patients with T1b gallbladder carcinomas, there was a 15.6% incidence of regional lymph node metastasis.49 Of 867 patients with a T2 primary lesion, 56.1% had regional
lymph node metastases.49 The 453 patients with T3 tumors had a
74.4% incidence of regional lymph node metastases.49 The 5-year survival rate following extended cholecystectomy for AJCC stage II and
III gallbladder carcinoma ranges from 7.5 to 37%.4850,52,54,55 AJCC
stage II or III gallbladder carcinoma patients treated with simple
cholecystectomy alone had a 5-year survival rate of 0% compared
with 29% in those patients treated with extended cholecystectomy.54
Regional lymph node metastases and/or direct tumor invasion of the
hepatic parenchyma are indicators of poor prognosis with significant
reductions in 5-year overall survival rates associated with these pathologic findings.5658 Microscopically positive liver resection margins
also have a negative impact on survival because these patients had a
median survival of 8.9 months compared with 67.2 months for
patients with tumor-free margins.56 Preoperative helical CT scans and
intraoperative ultrasonography are used to assess the extent of direct
invasion into the hepatic parenchyma which assists with decisionmaking regarding the extent of liver resection necessary to clear all
disease. If adequate tumor-negative resection margins are attained, the
radicality of liver resection does not impact on survival as attested by
similar long-term survival rates following right lobectomy, extended
right lobectomy, right trisegmentectomy, and central bisegmentectomy
for gallbladder cancer.4850,5961 T1b patients are classified as stage I
in the AJCC system, but, arguably, with a 15.6% incidence of regional
lymph node metastases, long-term survival benefit may occur in a significant number of these patients who undergo an extended cholecystectomy (see Fig. 98.4).
All authors do not perform an en-bloc resection of the extrahepatic bile duct as part of an extended cholecystectomy. Because gall-

Figure 98.4. Algorithm to guide surgical decision making for patients with gallbladder cancer. *Regional lymphadenectomy includes complete dissection
and removal of the cystic, pericholedochal, pancreaticoduodenal, gastrohepatic, and para aortic lymph nodes.

bladder carcinoma is found to invade the extrahepatic bile duct in 57%

of cases, with almost all cases occurring in patients with T3 or T4
tumors, an en-bloc resection of the proper hepatic and common bile
ducts with Roux-en-Y hepaticojejunostomy should be included in an
extended cholecystectomy of transmurally invasive tumors. This
includes those cases in whom a clinically unsuspected gallbladder carcinoma is diagnosed pathologically following a simple cholecystectomy with a positive margin at the cystic duct. Gallbladder cancer
involving the cystic duct and gallbladder neck frequently grows along
the proper hepatic and right bile ducts necessitating a right or
extended right hepatic lobectomy and excision of the extrahepatic
ducts to remove all disease.62
Extremely radical operations have been proposed for patients with
extensive T3N1M0 or T4N0-1M0 tumors. This includes hepatopancreaticoduodenectomy and abdominal organ cluster transplantation for
locally advanced gallbladder carcinoma.49,63,64 The operative mortality
rate for these radical procedures is at least 15% with a greater than 90%
incidence of major morbidity. Resection of the portal vein and/or hepatic artery with vascular reconstruction frequently is necessary to resect
completely all gross malignant disease. The largest report of patients
undergoing hepatopancreaticoduodenectomy for gallbladder carcinoma
is 150 cases from Japan, with a 5-year survival rate of 14%.49 The
patients who did not die from intraoperative or postoperative complications all succumbed to recurrent and/or metastatic carcinoma.
It is estimated that 70,000 laparoscopic cholecystectomies are
performed each year in the United States.65 On average, gallbladder
carcinoma is diagnosed in 2% of patients undergoing cholecystectomy for presumed benign biliary tract disease.2 Thus, approximately
1,400 patients who annually undergo laparoscopic cholecystectomy
could suffer inadvertent dissemination of gallbladder carcinoma.6571 The spillage of tumor cells at the time of laparoscopic
cholecystectomy has caused seeding of peritoneal surfaces and
laparoscopic port tracts in several patients.72,73 This dissemination of
tumor cells is an unfortunate occurrence because it may preclude a

potentially curative open resection and limit the patients long-term

survival. However, the potential laparoscopic dissemination of tumor
cells may not significantly alter the natural history of gallbladder cancer in most patients. A review of our experience at the University of
Texas M.D. Anderson Cancer Center with diagnostic and therapeutic
laparoscopy in patients with gastrointestinal malignancies indicated
that port site recurrence is a harbinger of widespread metastasis in
greater than 95% of patients, thus it is rarely an isolated site of recurrent malignant disease.74 Furthermore, a report drawn from the
National Cancer Data Base between 1989 and 1995 revealed no
change in incidence or survival from gallbladder cancer during the
time laparoscopic cholecystectomy supplanted open cholecystectomy
as the procedure of choice for gallbladder disease presumed benign.75
Nonetheless, because of the large number of cholecystectomies being
performed laparoscopically and the small but measurable risk of dissemination of tumor cells, it has been recommended that (1) unless
the surgeon feels capable of performing a definitive extended cholecystectomy for gallbladder carcinoma, patients in whom gallbladder
carcinoma is suspected preoperatively by clinical or radiologic criteria should be referred without laparoscopy, laparotomy, or percutaneous biopsy; and (2) if gallbladder carcinoma is suspected on visual
inspection during an attempted laparoscopic cholecystectomy, either
an open definitive operation should be performed or the operation
should be terminated without biopsy and the patient referred for
appropriate surgical therapy.66 Patients who underwent laparoscopic
cholecystectomy and were then found on pathologic analysis to have
gallbladder cancer should still be considered for aggressive surgical
treatment because long-term disease-free survival will result in a subset of these patients.76
Palliation. The majority of patients with gallbladder carcinoma
are diagnosed at an advanced, unresectable stage of disease. As in
patients with hilar bile duct cancer, relief of symptomatic jaundice is a
consideration. Patients with unresectable gallbladder carcinoma frequently have extensive involvement of the extrahepatic bile duct and

may have bulky porta hepatis lymphadenopathy, which makes endoscopic placement of an internal stent difficult. When unresectable gallbladder carcinoma is diagnosed at the time of laparotomy, a surgical
biliary bypass, such as an intrahepatic cholangioenteric anastomosis,
can be performed and results in significant symptomatic relief in
greater than 90% of patients.77 When the diagnosis is made on the basis
of radiographic and percutaneous biopsy findings, jaundice can be
relieved by placement of percutaneous transhepatic biliary catheters.
In contrast to patients with hilar bile duct carcinoma in which gastroduodenal obstruction is a relatively rare event, between 30 and 50%
of patients with advanced gallbladder carcinoma will develop a clinically significant element of gastroduodenal obstruction.78 This can be
treated surgically with a bypass procedure, such as gastrojejunostomy,
or by placement of a decompressing gastrostomy tube and feeding
jejunostomy tube. A percutaneous endoscopic gastrostomy tube also
can be used to decompress the obstructed stomach in patients with
advanced disease and limited expected survival.
Chemotherapy. Studies that describe the results of chemotherapeutic treatment for unresectable or metastatic gallbladder carcinoma
suffer from small numbers of patients and inclusion of patients with
hilar bile duct carcinoma. A study of 53 patients with gallbladder carcinoma who received systemic chemotherapy with 5-fluorouracil (5FU) or 5-FU plus other chemotherapeutic agents showed objective
antitumor responses in 12% or less of the patients in each treatment
arm.79 Fluoropyrimidines combined with doxorubicin administered
systemically have produced objective response rates of 30 to 40%.80,81
Gemcitabine as a single agent may produce similar response rates, but
these responses are rarely durable for more than 3 to 6 months.82 Complete remission is rare and transient following such systemic
chemotherapy regimens, and the median survival is 11 months or less.
The toxicities associated with these treatments are not insignificant,
and the survival benefit is only a few months greater than that of
patients who receive no treatment.
Hepatic arterial infusion chemotherapy also has been described in a
small number of patients with locally advanced gallbladder carcinoma.
Partial response rates of 55 to 60% and complete response rates of 9%
have been reported.8385 However, the median duration of response was
only 3 months, and all patients developed progressive disease. There
have been no patients who survived more than 4 years after beginning
hepatic arterial chemotherapy. The median survival of 12 to 14 months
with hepatic arterial infusion chemotherapy is not a major improvement
over the median survival in patients treated with intravenous chemotherapy. There may be less frequent and less severe systemic toxicity with
hepatic arterial infusion chemotherapy, but the magnitude of this benefit is slight and does not justify routine use of this approach to treat unresectable gallbladder carcinoma. Currently, there are no particularly compelling cytotoxic chemotherapeutic agents to treat locally unresectable
or metastatic primary hepatobiliary malignancies.
Radiation Therapy. Analysis of the patterns of failure after
resection of gallbladder carcinoma revealed that local recurrence was
the first and, in a significant number of cases, the only site of failure
in over one-half of patients.5,86 External-beam radiation therapy to a
total dose of 45 Gy can produce radiographic evidence of tumor reduction in 20 to 70% of these tumors and provide temporary relief of jaundice in up to 80% of patients.8789 In general, external-beam radiation
therapy is a palliative treatment. The median survival for locally
advanced gallbladder carcinoma patients treated with radiation therapy is approximately 10 months.8689 Occasional long-term survivors
are reported following treatment with higher doses of radiation therapy or with administration of radiation-sensitizing chemotherapeutic
agents such as 5-FU during external-beam radiation therapy.86 However, extrahepatic bile duct stricture has been reported in several of the
long-term survivors treated with high doses of radiation therapy.90
Intraoperative radiation therapy with a dose of 20 to 30 Gy has
been delivered to treat unresectable gallbladder carcinoma.91,92
Recanalization of obstructed extrahepatic bile ducts occurs in the
majority of patients treated with this technique. Intraoperative radiation therapy has not been associated with increased operative or postoperative morbidity in patients with unresectable tumors. The median
survival of patients treated with intraoperative radiation therapy is less

CHAPTER 98 / The Gallbladder 1419

than 12 months, and this treatment modality appears to palliate biliary

tract obstruction without significantly improving survival.
MULTIDISCIPLINARY APPROACHES The majority of patients who
undergo an extended cholecystectomy or more radical resection for
AJCC stage II, III, or IV gallbladder carcinoma develop tumor recurrence and die as a result of their disease. Nonrandomized studies and
case reports have suggested that overall survival can be improved by
administering adjuvant radiation therapy and/or chemotherapy after
resection of stage II, III, or IV tumors.93,94 Unfortunately, the number
of patients who have received postsurgical adjuvant treatment is small,
and a variety of treatment regimens have been used. In a nonrandomized study, 9 patients with stage IV gallbladder carcinoma were treated
with complete surgical resection alone, while 17 patients were treated
with complete resection combined with 20 to 30 Gy of intraoperative
radiation therapy.95 Ten of these 17 patients also received 36.4 Gy of
postoperative external-beam radiation therapy. The surgical procedures performed in both groups of patients included extended cholecystectomy and a variety of more radical procedures, including hepatopancreaticoduodenectomy. There were no 3-year survivors in the 9
patients treated with resection alone, but there was a 3-year survival of
10.1% in the 17 patients treated with resection and radiation therapy.
There is a single report of 18 patients treated with preoperative chemoradiation therapy (4,500 cGy, 180 cGy/fraction, 5 d/wk, continuous
intravenous infusion of 5-FU 350 mg/m2 /d on days 1 to 5 and 21 to 25)
prior to a planned resection of known gallbladder cancer.96 Thirteen of
the 18 patients underwent resection; 1 patient refused operation, 1
patient did not complete preoperative chemoradiation, 1 patient had
disease progression after chemoradiation, and 2 patients had unresectable disease found at laparotomy. The actuarial 5-year survival rate
in the 13 resected patients was 57%. Unfortunately, there are no randomized trials of patients with stage II and III gallbladder carcinoma
treated with a coherent program of adjuvant or neoadjuvant therapy.
Such trials will be necessary to demonstrate an improvement in survival in patients who receive pre- or postoperative therapies combined
with a curative resection for gallbladder carcinoma.
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