The Management of Gallbladder Cancer:
Before, During, and After Laparoscopic
Cholecystectomy
David B. Pearlstone, MD, Steven A. Curley, MD, and Barry W. Feig, MD
Carcinoma of the gallbladder is a rare disease, but when
encountered in the patient undergoing laparoscopic chole-
cystectomy, it can pose a number of dilemmas. Familiarity
with the risk factors for malignant gallbladder disease can
help identify patients in whom more extensive preopera-
tive evaluation is warranted. When carcinoma is identified
preoperatively, cholecystectomy should be performed as
an open procedure. If malignancy is encountered unexpect-
edly during laparoscopic cholecystectomy, the procedure
should be converted to an open resection to allow for
appropriate evaluation of the stage of disease and appropri-
ate surgical management. Most commonly, malignancy is
identified postoperatively, only after pathological examina-
tion of the resected gallbladder. Except in rare circum-
stances, open reoperation is necessary to achieve an ad-
equate curative resection. The current concerns about port
site recurrence and carcinomatosis after laparoscopic resec-
tion of a gallbladder carcinoma are unwarranted based on
current published data. The role of prophylactic excision or
irradiation of port sites is uncertain based on current
understanding of the biological behavior of the disease.
Copyright © 1998 by W. B. Saunders Company
Key words: Malignancy, neoplasm, port site recurrence,
carcinomatosis.
role of laparoscopy in the management of
r e
1 gallbladder malignancy is controversial. The
following two issues are at the core of the debate: (1)
does the technique of laparoscopy alter the behavior
of the tumor, either promoting carcinomatosis or
leading to trocar site recurrences; and (2) can an
appropriate oncological surgery be performed laparo-
scopically ?
Carcinoma of the gallbladder is rare, yet it is the
most common malignancy of the biliary tract and is
the seventh most common cancer of the gastrointes-
tinal tract. Gallbladder cancer has a striking differ-
ence in incidence between genders, occurring two to
three times more commonly in women than in
men.2-8 Worldwide, it accounts for less than 10% of
hepatobiliary cancers, but in the United States and
Western Europe, where the incidence of hepatocellu-
lar cancer is low, gallbladder cancer assumes a more
prevalent role among hepatobiliary malignancies.9 In
1998, it is estimated that 6,700 new cases of gallblad-
der cancer and other tumors of the extrahepatic
biliary tree will be diagnosed in the United States.1
The clinical presentation of carcinoma of the
gallbladder is notoriously indistinguishable from be-
nign biliary disease, with most patients presenting
with biliary colic and/or jaundice. Grossly, early
gallbladder cancers may be difficult to appreciate,
even in the resected specimen. Direct extension into
contiguous organs, including the liver (segments IV
and V), stomach, duodenum, and colon is not uncom-
mon in advanced cases. Vascular, perineural, and
lymphatic invasion may be evident microscopically,
and encasement of the hepatic artery and portal vein
can also occur.
Lymphatic drainage of the gallbladder is primar-
ily to cystic and choledochal nodes, celiac axis nodes,
and nodes within the aortocaval grove.&dquo; The cystic
duct node, located at the junction of the cystic and
proper hepatic ducts, is often the first site of lym-
phatic spread, and an enlarged cystic duct node
should be carefully scrutinized for evidence of malig-
nancy. Discontiguous liver metastases represent he-
matogenous spread; these liver lesions, along with
lung and bone metastases are rare and represent
advanced disease. < I
The vast majority of gallbladder cancers are adeno-
carcinomas, but squamous cell, adenosquamous, and
anaplastic types can occur.12 Lynzphoma,’3 carci-
noid,6,J4,15 small cell carcinoma,16 and sarcomas6,16,17
of the gallbladder have all been reported.
The treatment of carcinoma of the gallbladder is
dictated by stage, regardless of whether surgery is
performed open or laparoscopicly. American Joint
Committee on Cancer staging of gallbladder can-
cer’8 is shown in Table 1, but the older Nevin staging
system’9 is still commonly used (Table 2). Despite
isolated reports showing a benefit of adjuvant
therapy,2° the mainstay of therapy for carcinoma of
From the University of Texas M.D. Anderson Cancer Center, Houston,
TX.
Address reprint requests to Barry W. Feig, MD, Department of Surgical
Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Hol-
combe Blvd, Houston, TX, 77401.
Copyright &copy; 1998 by WB. Saunders Company
1071-5517/98/0502-0007~’8.00/0
121
122
Table 1. American Joint Committee on Cancer Staging
for Gallbladder Cancer
Used with permission of the American Joint Committee on
Cancer (AJCCO), Chicago, Illinois. The original source for this
material is the AJCC Manual for Staging of Cancer, 4th edition
(1992) published by Lippincott-Raven Publishers, Philadelphia.
the gallbladder is surgery.21 Chemotherapy and radia-
tion have consistently shown disappointing results in
this disease.2o,22-27
Reported survival rates are often markedly skewed
towards pTl lesions,28 likely due to the fact that
virtually all of these tumors were found incidentally
after cholecystectomy for lithic disease. Locally ad-
vanced disease, found either after preoperative evalu-
ation or incidentally, universally carries a dismal
prognosis. Although controversial, nodal disease
seems to be a poor prognostic sign and may dictate
further therapy.6,20,29-31 Survival data from the Na-
tional Cancer Institute’s Surveillance, Epidemiology,
and End Results study appropriately follows AJCC
staging: Stage 0% to 87%; stage I&horbar;60%; stage
II-25%; stage m&horbar;10%; stage IV-less than 2%.18
Gallbladder Carcinoma Detected Before
Laparoscopy
When gallbladder cancer is discovered before
surgery, traditional surgical management dictates
open operative intervention.6,!4,32-34 The overwhelm-
of
ing majority gallbladder cancers that are diag-
nosed before surgery are already in an advanced
stage (American Joint Committee on Cancer ill or
IV; Nevin V). Appropriate surgical treatment of
these lesions is controversial, 4,9,24 but most authors
agree that if surgical intervention for cure is war-
ranted at all, it requires &dquo;extended&dquo; or &dquo;radical&dquo;
cholecystectomy (resection of the gallbladder, the
hepatic bed of the gallbladder, and portal lymphad-
enectomy).5,6,24 Although the technology is available
to perform these procedures laparoscopically (eg,
laparoscopic ultrasound, ultrasonic dissector), very
few surgeons have the experience and laparoscopic
skills to adequately perform these procedures laparo-
scopically. Intraoperative radiation may also have
some benefit,27,35,36 but this procedure is not ame-
nable to a laparoscopic approach. Long-term survi-
vors after extensive liver resection for T4NO disease ’
have been reported,6 and there may be a role for
laparoscopy as a diagnostic modality in these cases to
assess extent of disease.37 In the rare case of early
gallbladder cancer being diagnosed preoperatively,
Table 2. Nevin Staging of Gallbladder Cancer

definitive staging is dependent on pathological exami-
nation of the entire fixed specimen. Although pTl
lesions may be adequately treated by simple cholecys-
tectomy,5,6,19,24,28,30,38 and this may be appropriately
performed laparoscopicly,28,39,40 the number of cases
in which early stage disease can be definitively
diagnosed preoperatively is extraordinarily small.
Even in these theoretical cases, principles of oncologi-
cal surgery mandate intraoperative assessment of
regional and distant metastatic disease. In the case of
carcinoma of the gallbladder, this requires assess-
ment of pericholedochal, celiac, and aortocaval lymph
nodes, as well as thorough assessment of the liver,
either by palpation and/or ultrasound. These proce-
dures require a surgeon skilled in advanced laparo-
scopic techniques if they are to be performed without
laparotomy.
’
Detection of gallbladder cancer preoperatively
requires a knowledge of which patients are at risk for
malignant biliary disease. Advanced age and female
sex have consistently been shown to be significant
risk factors for malignant versus benign biliary tract
disease/,14,4] although a female predominance has
not been observed in. all -series.12 An anomalous
pancreaticobiliary junction has been observed in up
to 10% of cases of gallbladder cancerll,42 and may
represent a risk factor for development of malig-
nancy. Ulcerative colitis has often been implicated as
a risk factor for gallbladder cancer, yet large series do
not bear this out. Although ulcerative colitis is associ-
ated with biliary tract disease, and even malignancy
of the extrahepatic biliary tree,43 Ritchie et al~ found
only 13% of these tumors were in fact gallbladder
cancer. Gallbladder cancer is more common in the
Hispanic population than in white or black popula-
tions45 and correlates with obesity, cholelithiasis, and
dietary habits among Hispanics.9 The incidence of
gallbladder cancer is highest among Southwestern
Native Americans, where it is six times that of
non-Native Americans, and is the second most com-
mon cancer of the gastrointestinal tract. 46-50 Inciden-
tal carcinoma of the gallbladder has been found in up
to 6% of Native Americans undergoing biliary sur-
gery,4~ compared with 2% to 3% among cholecystec-
tomy specimens in the general population. Although
the peak incidence of gallbladder cancer is in the
sixth and seventh decades of life, it has been reported
in almost all age groups. The youngest reported case
of gallbladder carcinoma occurred in an 11-year-old
Navajo girl.~’
Definitive causal relationships between environ-
mental factors and gallbladder cancer have not been
123
shown. There are suggestions, however, that certain
industrial compounds, including methylcholanthrene
and nitrosamines, may lead to a higher incidence of
gallbladder cancer among workers chronically ex-
posed to such agents.8~5~ Cholelithiasis, however, has
consistently been shown to be associated with carci-
noma of the gallbladder. The reported incidence of
gallbladder cancer found in autopsy specimens (pre-
sumably patients without signs or symptoms of be-
nign biliary disease) is less than 1%.4,53 Malignancy
among patients operated on for presumed benign
biliary disease, however, has been reported in 2% to
3% of cases.28,-l1,j4-j6 In a recent review of 456 cholecys-
tectomy specimens, resected for stones, polyps, or
adenomyomatosis, 13 (2.85%) malignant lesions were
found: ~1 The increased incidence of cholelithiasis and
cholecystitis among women may be the cause of the
higher incidence of carcinoma in women.57
Gallstone size also seems to be directly correlated
with the incidence of carcinomall,58; patients who
have gallstones greater than 3 cm in size exhibit a
10-fold increase in risk of harboring carcinoma.’9
Chronic cholecystitis often leads to calcification of
the wall of the gallbladder, producing a &dquo;porcelain
gallbladder&dquo;; it has been reported that as many as
22% of these patients develop carcinoma6O; however,
recent reports suggest a much lower incidence.37
Mirizzi syndrome, extrinsic compression of the
common hepatic duct by impacted gallstones within
the gallbladder in the setting of cholecystitis and
jaundice, has been found to be significantly associ-
ated with the presence of malignancy.~’ Serum mark-
ers for malignancy have also been investigated to
detect malignancy in patients presenting with biliary
disease,62 but with varying results. In Mori et al’s
analysis of 456 patients undergoing laparoscopic
cholecystectomy, carcinoembryonic antigen (CEA)
and CA19-9 levels were neither sensitive nor specific
for the detection of malignancy.41 Redaelli et al,
however, found that CA19-9 levels were significantly
higher in patients with malignancies than those with
Mirizzi syndrome.61
Preoperative ultrasound evaluation can more
readily detect polypoid mucosal lesions of the gallblad-
der than flat lesions,39 and those greater than 1 cm in
diameter have been shown to be associated with
malignancy.39,-l1,63,54 Sessile shape, isoechogenicitywith
the liver parenchyma, and rapid growth have also
been found to be signs of malignancy in gallbladder
polyps detected preoperatively by ultrasound.39 When
lesions of this type are detected preoperatively, the
suspicion of malignancy must be high and the case
124
should be approached as open cholecystectomy. Lap-
aroscopic cholecystectomy can be used for lesions
that have a low suspicion for malignancy.6’
Identification of high-risk patients will often lead
to a more extensive preoperative work-up, but again
malignancy is difficult to appreciate by radiological
techniques.24,28,66,67 Sonography may detect advanced
disease in up to 70% of cases, but the sensitivity of
transabdominal ultrasound in detecting early disease
is variable.5,39,42,68-70 A computed axial tomography
scan has often been used in evaluating patients with
suspected malignancy, but it has not consistently
been accurate in clearly identifying gallbladder tu-
mors. ]4,31,42 Cholangiography is of little value in
detecting malignancy but may help in planing opera-
tive intervention.42 Dynamic magnetic resonance
imaging shows some promise in differentiating be-
nign from malignant disease, but is only beginning to
be evaluated. 71 Color Doppler ultrasound has also
recently been used preoperatively to differentiate
benign from malignant disease with some degree of
success.72,73 Further refinements of these techniques
may lead to better preoperative detection of malig-
’
nancy in the future..
Gallbladder Carcinoma Detected During
Laparoscopic Cholecystectomy
When malignancy is encountered during laparo-
scopic cholecystectomy, the case should be converted
to an open procedure 14,32,33,70,74 for appropriate evalu-
ation of regional and metastatic disease and to allow
for an appropriate oncological resection. Level of
surgical dissection is dictated by the stage of the
disease. As discussed previously, Tl lesions can be
adequately treated by simple cholecystectomy; and,
again, this may be accomplished laparoscopicly, al-
though some authors have firmly stated that laparo-
scopic cholecystectomy should never be performed
for malignancy,75 Lesions proven to be T2 or greater
intraoperatively require more radical resection and
should be converted to an open procedure unless the
surgeon is skilled in laparoscopic ultrasound and
other advanced laparoscopic techniques. 28
In cases in which there is a suspicion of malig-
nancy raised during laparoscopic cholecystectomy,
operative biopsy and frozen section diagnosis should
be obtained. All cholecystectomy specimens should
be opened in the operating room by the operating
surgeon and the mucosa of the gallbladder should be
carefully examined.22,28,74 Laparoscopy limits the role
of palpation in assessing tissues for the presence of
malignancy, 70 further emphasizing the importance of
intraoperative examination of the removed gallblad-
der. Early stage gallbladder cancers, appearing as
ulcerations or small plaques, may be subtle on gross
examination of the opened specimen. The wall of the
gallbladder may be firm and thickened, making it
difficult to distinguish an early gallbladder cancer
from changes secondary to cholecystitis. Gallstones
are commonly present. More advanced lesions ap-
pear as firm masses that infiltrate through the full
thickness of the gallbladder wall.
Gallbladder Carcinoma Discovered After
Laparoscopic Cholecystectomy
Gallbladder cancer is most commonly diagnosed
only after pathological examination of the specimen.
Again, Tl lesions are likely adequately treated by
simple cholecystectomy, whether performed laparo-
scopicly or open. Lesions extending beyond the peri-
muscular layer of the gallbladder wall (?T2) should
at a minimum be treated by resection of the gallblad-
der bed with a margin of normal liver tissue and
appropriate ly-mphadenectomy. 21,11 The anatomic lo-
cation of a T2 lesion within the gallbladder, however,
may influence the extent of further surgical resection
required for these lesions. 77 The &dquo;standard&dquo; radical
resection advocated by Shirai et a1.30 includes resec-
tion of the extrahepatic biliary tree, but most centers
preserve the extrahepatic bile ducts during radical
resection. Some authors have advocated radical resec-
tion for T 1 b lesions.31,78 More extensive resections
have also been advocated for selected patients with
locally advanced disease 6,30,31,38,79 or discontiguous
liver metastases.e° Evaluation of the cystic duct node,
often included in simple cholecystectomy specimens,
may provide valuable staging information.19 Debate
over the appropriate level of resection will continue,
but one point is clear: cure of any gallbladder cancer
that extends into the perimuscular layer of the
gallbladder wall or beyond removed by laparoscopic
cholecystectomy requires more extensive surgery.
Recurrence of malignant disease in trocar sites
after laparoscopic manipulation or resection of malig-
nancy has been the subject of considerable recent
controversy. The surgical literature has become inun-
dated by case reports of metastatic disease occurring
in laparoscopic wounds, 14,33,34,67,70,74,76,81-106 but there
is a notable lack of scientific evaluation of this
phenomenon. Gallbladder carcinoma has been one
the most often cited tumors found to implant at
trocar sites presumably because of the fact that
cholecystectomy is the most common laparoscopic

procedure performed by general surgeons. Reports of
wound recurrences after open procedures for malig-
nancy are rare in the literature, despite studies that
have shown laparotomy to have a significant effect on
tumor growth. 107-110 In a recent review of our experi-
ence at the University of Texas M.D. Anderson
Cancer Center, the records of 93 patients with
gallbladder cancer were reviewed. Of these patients,
21 had previously undergone laparoscopic cholecystec-
tomy, 26 had undergone open cholecystectomy, and
16 had undergone a laparoscopic procedure that was
converted to an open procedure. Wound recurrences
occurred in six of the laparoscopic cholecystectomy
patients (29%) and eight of the open cholecystectomy
patients (31%). Five abdominal recurrences were
noted in the patients who were converted from
laparoscopic procedures to open procedures, four in
the laparotomy incision, and only one in the laparos-
copy wounds. There was no statistically significant
difference in the incidence of wound recurrence
among these groups. 16 The many case reports of port
site recurrence notwithstanding, these data indicate
that there is no increased risk of abdominal wall
recurrence after laparoscopic cholecystectomy com-
pared with open cholecystectomy in cases of gallblad-
der carcinoma. The actuarial 5-year overall survival
for all patients was 10%; there was no significant
difference in survival based on the method of cholecys-
tectomy.~6 It is also important to note that despite
the increase in the number of cholecystectomies
performed since the introduction of laparoscopy, and
the lower mean age of the patients undergoing the
procedure, there has not been a resultant increase in
the proportion of early stage cancers being detected,
nor has there been any impact on survival. Wound
recurrence after surgery for gallbladder cancer seems
to be a reflection of the underlying biology of the
disease, rather than a reflection of the surgical
technique used.
An increased incidence of disseminated intra-
abdominal disease after laparoscopic cholecystec-
tomy has been implied, but this is also supported only
by anecdotal reports. Our experience at the Univer-
sity of Texas M.D. Anderson Cancer Center indi-
cates that laparoscopy does not influence the develop-
ment of carcinomatosis. In 137 patients with gastric
adenocarcinoma who underwent laparoscopy as part
of their treatment at our institution, the incidence of
carcinomatosis among these patients was not in-
creased when compared with 66 gastric cancer pa-
tients who did not undergo laparoscopy.111 I
Many authors have advocated full thickness resec-
125
tion of the abdominal wall around the port site from
where a malignant specimen was removed, or even
resection of all port sites, if an incidental gallbladder
cancer is discovered after laparoscopic cholecystec-
tomy.6,28,32,74,82,112 This practice has not been shown to
influence the incidence of tumor recurrence in the
abdominal wall, the time to recurrence, or the overall
survival of the patient. Indeed, this practice is not
consistent with our current understanding of tumor
biology and tumor cell growth. Many of the reported
port site recurrences have occurred at port sites that
had no contact with the specimen. In these cases, the
removal of &dquo;contaminated&dquo; instruments through tro-
cars has been implicated in seeding tumor cells in the
site. More likely, these port site recurrences repre-
sent hematogenous deposition of systemicly circulat-
ing tumor cells in healing wounds, a favored site for
growth of metastatic disease. In this case, resection of
the port site would seem to merely create another,
larger wound for the development of recurrence.
The use of nonporous extraction bags have been
advocated as a means of preventing peritoneal seed-
ing.28,I02 Although this additional maneuver may help
avoid spillage of potentially malignant cells, studies
have documented the development of port site metas-
tases even when extraction bags were used. 74,76 These
cases lend further evidence to the theory that port
site metastases are a product of deposition of sys-
temicly circulating tumor cells, rather than &dquo;wound
inoculation.&dquo;
Inadvertent gallbladder disruption with spillage of
intraluminal contents into the peritoneal cavity is an
easily avoidable problem. Although not proven, spill-
age of malignant cells into the peritoneum may lead
to diffuse peritoneal disease and has been reported to
occur more often during laparoscopic cholecystec-
tomy than open cholecystectomy.6,14-,28,32,51,74 Care
must be taken to avoid this event. Widening the port
site incision through which the specimen is removed’ 13
and the use of an extraction bag may decrease the
possibility of widespread dissemination.34,75
Conclusions
Gallbladder cancer is an insidious disease, the
outcome of which is highly dependent on the method
and timing of detection of the tumor. With the
possible exception of very early stage lesions, malig-
nancies of the gallbladder, whether discovered preop-
eratively, intraoperatively, or postoperatively require
open surgical intervention if there is to be any chance
of cure. The use of laparoscopy itself does not seem to
126
affect the outcome of patients with incidentally
discovered gallbladder cancer, but it has yet to be
shown to be an adequate method of treatment for
advanced stages of the disease.
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