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Section VIII Biliary Tract

intra- or and extrahepatic metastases, and nonresectability.

Patients with PSC are considered nonresectable as described
earlier.

Chemotherapy, Radiation Therapy,

and Targeted Therapy
No curative medical therapies for cholangiocarcinoma are
available. A variety of chemotherapeutic agents such as gemcitabine, other antimetabolites, taxanes, platinum analogs,
anthracyclines, and mitomycin have been evaluated as single
or combination therapies. The only chemotherapeutic drug
approved by the FDA for cholangiocarcinoma is gemcitabine.
In 2010, the Advanced Biliary Cancer-02 (ABC-02) trial67
showed a statistically signicant 3-month overall and
progression-free survival benet for gemcitabine-oxaliplatin
combination therapy compared with gemcitabine alone. The
only adverse effect that was more severe in patients in the
combination treatment arm was hematologic toxicity; however,
patients with cirrhosis were not included in the trial.67 Therefore, gemcitabine plus oxaliplatin has become the standard
of care for unresectable cholangiocarcinoma in noncirrhotic
patients.
No large randomized controlled trials have evaluated the
benet of radiation therapy in unresectable cholangiocarcinoma. Therefore, the use of radiation therapy remains
controversial.2
Targeted agents have achieved signicant prolongation of
survival when used to treat other cancers, such as hepatocellular carcinoma and renal cell carcinoma. Targeted agents (i.e.,
EGFR inhibitors) are being evaluated in combination with chemotherapeutic agents,68 but large randomized controlled trials
in patients with cholangiocarcinoma are currently lacking and
will require survival, rather than tumor response alone, as the
primary end point.

Palliative Treatment
Patients with cholangiocarcinoma commonly experience cholestasis, abdominal pain, and cachexia, which limit the quality
of life. Therefore, palliative treatments are essential in the
management of patients with cholangiocarcinoma. Options
for restoration of biliary drainage include endoscopic, percutaneous, and surgical techniques. Endoscopic and percutaneous methods are based on placement of biliary stents (see
Chapter 70), whereas surgical approaches create a bypass via
a choledocho- or hepaticojejunostomy. The efcacies of similar
endoscopic and surgical approaches are similar, but the mortality rate, frequency of procedure-related complications, and
duration of hospital stay are higher for surgical palliation.69
The decision to pursue endoscopic or percutaneous biliary
stent deployment is based on the anatomic location of the
malignant stricture (see Chapter 70). Although unilateral restoration of bile ow is in general sufcient, bilateral restoration of biliary drainage has been associated with increased
survival.70,71 Cross-sectional imaging is critical before a stent is
placed to avoid attempts at endoscopic drainage of an atrophic
lobe or a lobe in which adequate drainage is not feasible. Retrograde injection of dye without drainage carries a high risk
of iatrogenic bacterial cholangitis, which can be severe. Early
intervention in a patient with malignant biliary obstruction is
recommended because the time to normalization of the serum
bilirubin level doubles from 3 to 6 weeks when the serum total
bilirubin level is greater than 10 mg/dL.72
Photodynamic therapy (PDT) has been shown to be a
feasible palliative treatment option that reduces cholestasis, improves quality of life, and possibly provides a survival benet similar to R1/R2 resection.73-75 PDT involves the

systemic application of a photosensitizing agent (e.g., hematoporphyrin), followed by localized illumination of the tumor
at a specic wavelength. Tumor cell cytotoxicity is achieved
through reactive oxygen speciesmediated cell death, tumorvessel thrombosis, and tumor-specic immune reactions.
Safety concerns have been raised, however, and the routine
use of PDT is not recommended by the British Society of
Gastroenterology.76
External beam radiation and intraoperative or intraductal
brachytherapy have been suggested for palliative treatment.77
No large, prospective randomized controlled trials providing
sufcient evidence for the use of these techniques in cholangiocarcinoma, however, have been conducted. Although a few
retrospective studies have suggested a survival benet with
transarterial chemoembolization (TACE), no large, prospective randomized controlled trials providing sufcient evidence for the efcacy of TACE, or other locoregional therapies,
in cholangiocarcinoma have been performed.76

GALLBLADDER CARCINOMA
Gallbladder carcinoma is the second most common primary
biliary malignancy and the fth most common malignancy of
the GI tract. Like other biliary malignancies, gallbladder carcinoma is diagnosed at an advanced stage in the majority of
cases. In only one third of the cases is a diagnosis of gallbladder carcinoma made prior to surgical exploration.78 The growth
kinetics of gallbladder carcinoma are faster than those for
cholangiocarcinoma, and, in general, gallbladder carcinoma is
diagnosed at a later stage than ampullary carcinoma (see
later). Gallbladder carcinoma is not amenable to medical or
radiation therapy, and surgical resection is the only potentially
curative treatment. Unfortunately, only a minority of patients
are surgical candidates at the time of diagnosis. The prognosis
of gallbladder carcinoma is dismal, with 5-year survival rates
of 0% to 10% and a median survival of less than 6 months.
More aggressive surgical approaches have been advocated.

Epidemiology
The distribution of gallbladder carcinoma is geographically
heterogeneous, with the highest incidence rates (up to 21.5 per
100,000 population) observed in India. Incidence rates are also
high in South America, Asia, and certain Eastern European
countries such as Poland.79 Gallbladder carcinoma is rare in
Western European countries and the United States, where the
National Cancer Institute reported an age-adjusted incidence
rate of 1.2 per 100,000 in 2007. Global incidence rates of gallbladder carcinoma parallel the incidence rates of cholelithiasis. With the exception of Japan, where the incidence has
increased, age-adjusted incidence rates of gallbladder carcinoma have remained relatively stable in most countries since
the 1970s.79 Ethnic differences in the incidence of gallbladder
carcinoma have been described within the United States, with
higher rates in Caucasians than in African Americans. Mortality rates also vary globally. The age-adjusted mortality rate in
the United States between 2000 and 2005 was 0.7 per 100,000,
with an overall decrease since 1990.6 The highest mortality rate
(35 per 100,000) was reported in southern Chile.80 The average
age at diagnosis is 65 years, and the peak incidence is observed
in the seventh and eighth decades of life. Globally, there is a
female predisposition to gallbladder carcinoma.79

Etiology
The cause of gallbladder carcinoma is not well understood
but is thought to be multifactorial. Several risk factors for

Chapter 69 Tumors of the Bile Ducts, Gallbladder, and Ampulla

BOX 69-3 Risk Factors for Gallbladder Carcinoma

Anomalous union of the pancreaticobiliary ductal system
Carcinogens*
Cholangiocarcinoma
Cholelithiasis (stone size > 1 cm)
Chronic Salmonella Typhi or Paratyphi carrier status
First-degree relative with gallbladder cancer
IBD
Intrahepatic biliary dysplasia
Lynch syndrome
Porcelain gallbladder
PSC
Segmental adenomyomatosis in patients 60 years of age
*Methylcholanthrene, O-aminoazotoluene, nitrosamines, possibly others.

gallbladder carcinoma have been described (Box 69-3). The

primary risk factor for gallbladder carcinoma is cholelithiasis
(see Chapter 65). Gallstones are found in 65% to 90% of
patients with gallbladder carcinoma. Populations with high
rates of cholelithiasis also have high rates of gallbladder carcinoma. Autopsy-based studies from Chile have suggested a
7-fold increased risk of gallbladder carcinoma in patients with
cholelithiasis, whereas epidemiologic studies in the United
States have observed only a marginally signicant 3-fold
increased risk of gallbladder carcinoma in men with cholelithiasis.81,82 Gallbladder carcinoma actually develops in only
1% to 3% of patients with cholelithiasis, and 20% of patients
with gallbladder carcinoma do not have evidence of cholelithiasis. Therefore, a prophylactic cholecystectomy in an
asymptomatic patient with gallstones to prevent gallbladder
carcinoma cannot be recommended. A positive correlation
between the risk of gallbladder carcinoma and the size and
number of gallstones has been reported but likely reects the
duration of cholelithiasis.83 No differences in the risk of gallbladder carcinoma have been observed with different types of
gallstones. Porcelain gallbladder (extensive calcication of the
gallbladder wall) is a classic, although controversial, risk
factor for gallbladder carcinoma.84 Although an increased risk
of gallbladder carcinoma has been reported in patients with a
porcelain gallbladder, the risk may be limited to patients with
selective mucosal calcication (types II and III porcelain gallbladder) rather than those with diffuse mucosal calcication
(type I).85
Adenomatous polyps of the gallbladder constitute another
risk factor for gallbladder carcinoma (see Chapter 67). The risk
correlates positively with the size, type, and growth rate of the
polyps. Patients with polyps that are greater than 1 cm in size,
sessile, and associated with gallstones, exhibit a rapid increase
in size, demonstrate arterial ow on Doppler US, or are symptomatic are at increased risk of malignant transformation and
warrant prophylactic cholecystectomy.84,86
Anomalous union of the pancreaticobiliary ductal system
(AUPBD) has been associated with the development of gallbladder carcinoma (see Chapter 55). In this congenital defect,
the pancreatic and bile ducts unite outside the duodenal wall
in a long common channel. The anomaly is found incidentally
in 1.5% to 2% of patients who undergo ERCP and leads to
cholestasis and reux of pancreatic secretions into the gallbladder, with resulting chronic inammation of the mucosa.
Approximately 10% of patients with gallbladder carcinoma
have coexisting AUPBD, and gallbladder carcinoma develops
in 15% to 40% of those with AUPBD. Patients with an associated choledochal cyst have a lower frequency of gallbladder
carcinoma than those without a choledochal cyst.87 Patients
with AUPBD are usually 10 years younger at the time of

1193

diagnosis of gallbladder carcinoma and have a lower frequency of cholelithiasis than those without AUPBD. On the
basis of the signicantly increased risk of gallbladder carcinoma, several Japanese hepatobiliary oncology associations
have recommended prophylactic cholecystectomy in patients
with AUPBD.84
PSC has been associated with gallbladder carcinoma, and
studies have reported that adenocarcinoma of the gallbladder
develops in up to 20% of patients with PSC and that 40% to
60% of gallbladder masses in patients with PSC are malignant.88,89 Therefore, patients with PSC and a gallbladder mass
of any size should undergo cholecystectomy or be monitored
closely for gallbladder carcinoma.
Adenomyomatosis of the gallbladder is characterized by
microscopic invaginations (Rokitansky-Aschoff sinuses) of the
mucosa with cyst formation in the muscularis propria (see
Chapter 67). A large Japanese study showed an increased incidence of gallbladder carcinoma in patients 60 years of age or
older with segmental adenomyomatosis of the gallbladder.90
In general, however, adenomyomatosis is viewed as a benign
condition.
Other conditions associated with gallbladder carcinoma
include IBD, intrahepatic biliary dysplasia, and cholangiocarcinoma.89 Chronic carriers of Salmonella Typhi or Paratyphi
have been shown to be at increased risk for the development
of gallbladder carcinoma.91 Other bacteria such as Escherichia
coli and Hp have also been associated with gallbladder carcinoma, but the data are not conclusive. First-degree relatives
of patients with gallbladder carcinoma have a relative risk
of 13.9 for developing this malignancy.92 Carcinogens, including methylcholanthrene, O-aminoazotoluene, and nitrosamines, have been identied in animal models of gallbladder
carcinoma. Other potential carcinogens include mustard
oil, products of free radical oxidation, and secondary bile
acids.93 Obesity has been suggested to be a risk factor for gallbladder carcinoma, especially in women,94 but the independence of obesity from cholelithiasis as a risk factor has not
been shown.

Pathology
From 80% to 95% of gallbladder carcinomas are adenocarcinomas; the majority of these are moderately to well differentiated.80 Adenocarcinomas are further divided into papillary,
tubular, and nodular variants, with the papillary adenocarcinomas being the least aggressive form.95 Less common types,
in order of frequency, include undifferentiated or anaplastic
carcinoma, squamous cell carcinoma, and adenosquamous
carcinoma. Rare types include carcinoids, small cell carcinomas, malignant melanomas, lymphomas, and sarcomas.93
Sixty percent of gallbladder carcinomas are located in the gallbladder fundus, 30% in the body, and 10% in the gallbladder
neck.95 Analogous to cholangiocarcinoma, the papillary form
of gallbladder carcinoma has a lower potential for invasion
and metastatic spread to lymph nodes.96 Gallbladder carcinoma spreads via direct invasion, lymphatic or hematogenous
metastasis, perineural invasion, and intraperitoneal or intraductal invasion. Lymphatic tumor cell spread is determined
by the physiologic gallbladder lymphatic plexus, including
the rst-level lymph nodes along the biliary tract (cystic duct,
bile duct, and hepatic duct), followed by pancreaticoduodenal
lymph nodes, as well as lymph nodes along the common
hepatic artery and celiac axis. Lymph node metastases are
described in 54% to 64% of patients and correlate with the
depth of invasion. Gallbladder carcinoma has a predisposition
to involve the liver bed because of venous drainage, predominantly into hepatic segments IVb and V (see Chapter 71),
and the anatomic approximation that allows direct hepatic

1194

Section VIII Biliary Tract

invasion. Perineural spread is observed in 24% and intraductal

spread in 19% of cases.

Pathogenesis
Gallbladder carcinoma can develop from foci of mucosal dysplasia or carcinoma in situ that progress to adenocarcinoma or
from an adenoma-carcinoma sequence similar to that seen
with colon cancer (see Chapter 127).97 Foci of dysplasia and
carcinoma in situ are frequently found adjacent to gallbladder
carcinoma in surgically resected gallbladder specimens and
are thought to be precursors of invasive adenocarcinoma.80
The time of progression of dysplasia to carcinoma is estimated
to be 10 to 15 years.98 Like cholangiocarcinoma, the major
pathogenic factor is inammation. Increased iNOS and COX-2
expression has been demonstrated immunohistochemically in
gallbladder carcinoma samples as well as in hyperplastic gallbladder mucosa from patients with AUPBD and also has been
associated with TP53 tumor suppressor gene mutations in
patients with gallbladder carcinoma. High expression and
mutation rates of the TP53 gene have been demonstrated in
35% to 92% of gallbladder carcinomas, 86% of carcinomas
in situ, and 28% of dysplastic foci, supporting an early role
for TP53 mutation in the dysplasia-carcinoma progression
sequence.99,100 Mouse double minute 2 homolog (MDM2) overexpression, which can result in functional inactivation of p53,
has been described in up to 80% of gallbladder carcinomas.101
Immunohistochemical studies have also found other cell cycle
regulatory proteins to be aberrantly expressed in gallbladder
carcinomas and its precursor lesions. Reduced expression of
the cell cycle inhibitor p27Kip1 was reported in 43% to 83% of
gallbladder carcinomas, and its decreased expression was an
independent prognostic factor for higher TNM stage, lymph
node metastasis, and shorter survival.101,102 Reduced expression of p21WAF1/Cip1 was observed in 49% to 68% of gallbladder
carcinomas, 43% of adenomas, and 100% of gallbladder
dysplasia; in patients with gallbladder carcinoma, reduced
p21WAF1/Cip1 expression was correlated with shorter diseasefree and overall survival.101,103 In up to 60% of patients with
gallbladder carcinoma, mutations of the K-ras oncogene have
been detected; the frequency is highest in patients with
AUPBD.104 Single studies have reported up-regulation of
EGFR, HER2/ErbB2, and the nm23 metastasis suppressor
protein.105,106 In a comparative study, up-regulation of EGFR
and HER2 was observed, respectively, in 39% and 10% of
gallbladder carcinomas, 100% and 10% of intrahepatic cholangiocarcinomas, and 53% and 26% of extrahepatic cholangiocarcinomas, thereby illustrating the differences among the
types of biliary tract carcinomas.107 Mutations and increased
expression of the nuclear oncogene that encodes p16INK4 have
been shown in several studies.108 Other studies have demonstrated loss of heterozygosity or microsatellite instabilities in
chromosomal regions that harbor known or putative tumor
suppressor genes.109

Clinical Features and Diagnosis

In 47% to 78% of patients, gallbladder carcinoma is found
incidentally during cholecystectomy for presumed benign
disease, reecting the initial clinically silent nature of this
malignancy.110,111 Incidentally diagnosed gallbladder carcinomas generally are lower in stage than symptomatic carcinomas at the time of diagnosis and are associated with better
median survival rates.111
Common clinical presentations include biliary or abdominal pain and jaundice secondary to direct invasion of the
biliary ducts or metastasis to the hepatoduodenal ligament.
Weight loss, abdominal distention, or other symptoms

resulting from compression or invasion of adjacent organs

indicate more advanced disease.
CEA and CA 19-9 are the most commonly used tumor
markers for gallbladder carcinoma. At a cutoff at 4.0 ng/mL,
an elevated serum CEA level has a sensitivity and specicity
of 50% and 93%. The sensitivity and specicity of an elevated
serum CA 19-9 level at a cutoff of 20 U/mL are 79% and
79%.112,113 As indicated earlier, these tests aid in diagnosis but
should not be relied on because levels can be elevated in
inammatory conditions and gastroenterologic and gynecologic malignancies; moreover, a subset of the population does
not produce CEA.
Abdominal US is often one of the rst imaging studies
performed in a patient who presents with the aforementioned
symptoms. The sensitivity and accuracy of US for gallbladder
carcinoma are 85% and 80%, respectively; early cancers, especially sessile polyps, can be missed. Typical imaging presentations of gallbladder carcinoma include focal or diffuse mural
thickening of the gallbladder, an intraluminal mass greater
than 2 cm in size that originates in the gallbladder wall, and
a subhepatic mass that replaces or obscures the gallbladder
and often invades adjacent organs (Fig. 69-6). Findings indicative of the malignant nature of a gallbladder lesion include
irregular, asymmetrical mural thickening greater than 1 cm in
depth and a nodular or smooth intraluminal mass greater than
1 cm in size, with xation to the gallbladder wall, that is not
displaced by the patients movements and has no acoustic
shadow. In indeterminate cases, Doppler US can be attempted
to differentiate a malignant from a benign gallbladder lesion
on the basis of the pattern of the color signal, blood ow velocity, and resistive index (a measure of resistance to arterial
blood ow).114 MRI and CT can be helpful in the diagnosis if
the US ndings are indeterminate. Helical CT has an 83% to
86% accuracy in assessing the local extent, with better performance in T2 and higher stages (see later), and is, therefore,
helpful in preoperative planning.115,116 The role of PET in gallbladder carcinoma is evolving and not routine.117 The sensitivity of PET for detecting gallbladder carcinoma is only 75% to
78%.118,119 Its main impact is in the detection of distant metastases that result in a change in management.44

Staging
Staging systems for gallbladder carcinoma include the NevinMoran classication system and the Japanese Biliary Surgical
Society staging system. The most commonly used staging
system is the TNM system described by the AJCC and UICC
(Table 69-6). The TNM-based staging system correlates with
survival. Reported 5-year survival rates for patients with
stages 0, I, II, III A, III B, IV A, and IV B gallbladder carcinoma
are 80%, 50%, 28%, 8%, 7%, 4%, and 2%, respectively. In the
2009 version of the AJCC/UICC staging system, stage T1b in
the previous version was redened as T2.47 In comparing different prognostic and therapeutic studies, it is important to
account for differences in the version of the applied staging
system.

Treatment
Surgery is the only potentially curative therapeutic option for
gallbladder carcinoma. Only 15% to 47% of patients are candidates for surgical resection at the time of diagnosis because
the stage of the disease is advanced in most cases. Contraindications to resection include multiple hepatic or distant
metastases, gross vascular invasion or encasement of major
vessels, malignant ascites, and poor functional status.95 Direct
invasion of the colon, duodenum, or liver is not considered an
absolute contraindication to surgical resection. The goal of

Chapter 69 Tumors of the Bile Ducts, Gallbladder, and Ampulla

1195

TABLE 69-6 TNM and American Joint Committee on

Cancer (AJCC)/International Union Against Cancer (UICC)
Staging Systems for Gallbladder Carcinoma
TNM Stage

Criteria

Tx
T0
Tis
T1a
T1b
T2

M0
M1

Primary tumor cannot be assessed

No evidence of primary tumor
Carcinoma in situ
Tumor invades lamina propria
Tumor invades muscularis propria
Tumor invades perimuscular connective
tissue without extension beyond serosa
or into liver
Tumor perforates the serosa AND/OR
Tumor directly invades the liver AND/OR
Tumor invades one other adjacent organ
(i.e., stomach, duodenum, colon,
pancreas, omentum, extrahepatic bile
ducts)
Tumor invades the portal vein or hepatic
artery OR
Tumor invades 2 extrahepatic organs or
structures
Regional lymph nodes cannot be assessed
No regional lymph node metastases
Lymph node metastases along the cystic
duct, bile duct, hepatic artery, AND/OR
portal vein
Metastases to periaortic, pericaval,
superior mesenteric artery, AND/OR
celiac artery lymph nodes
No distant metastases
Distant metastases

AJCC/UICC
Stage

Tumor

Node

Metastasis

Tis
T1
T2
T3
T1-3
T4
Any T
Any T

N0
N0
N0
N0
N1
N0-1
N2
Any N

M0
M0
M0
M0
M0
M0
M0
M1

T3

T4

Nx
N0
N1

N2

0
I
II
III A
III B
IV A
IV B

TNM, tumor, node, metastasis.

C
FIGURE 69-6. Imaging of gallbladder carcinoma. A, Axial CT view
of the abdomen. Cholelithiasis is seen inferior to the gallbladder
mass (arrow). B, Coronal view of the same patient. C, US in the
same patient showing a large mass (arrow) originating from the
gallbladder wall and protruding into the lumen.

surgical treatment is an R0 resection, dened as negative

margins and nodal dissection one level past microscopically
involved lymph nodes. R0 resection in gallbladder carcinoma
has been shown to correlate with survival and with signicantly increased 5-year survival rates110,120; however, R0

resection is achieved in only 36% to 49% of patients undergoing surgical exploration or reexploration.110,121
Surgical procedures with curative intent include (1) simple
cholecystectomy; (2) extended or radical cholecystectomy
with additional resection of greater than 2 cm of the gallbladder bed plus lymphadenectomy of the hepatoduodenal ligament behind the second part of the duodenum, head of the
pancreas, and celiac axis; (3) extended cholecystectomy with
hepatic, segmental, or lobar resection; (4) extended cholecystectomy with extensive para-aortic lymph node resection; and
(5) extended cholecystectomy with bile duct resection or pancreaticoduodenectomy. The surgical approach is dictated by
the extent of tumor. Less than 10% of patients with gallbladder
carcinoma are diagnosed with Tis and T1a tumors. At these
stages, gallbladder carcinomas can be treated with simple cholecystectomy, with 5-year survival rates of 85% to 100%. A few
reports have also favored simple cholecystectomy for stage 1b
gallbladder carcinoma and have reported similar survival
rates after either simple or radical cholecystectomy.122,123 Up

1196

Section VIII Biliary Tract

to 15% of patients with stage 1b gallbladder carcinoma,

however, are positive for lymph node metastases, compared
with 2.5% of patients with stage 1a gallbladder carcinoma.124
Also, higher recurrence rates have been observed after simple
(vs. radical) cholecystectomy; therefore, radical cholecystectomy is recommended for stage 1b gallbladder carcinoma.124-127
Invasion of the muscularis propria, as in stage T2 tumors,
requires radical cholecystectomy, resulting in 5-year survival
rates of 59% to 90% compared with 17% to 40% with simple
cholecystectomy.128-130 The surgical approach to stage T3 and
T4 tumors is controversial. Some studies have shown no
5-year survival benet after radical cholecystectomy for stage
T3 and T4 tumors, but other studies have reported 5-year
survival rates of 15% to 63% and 7% to 25%, respectively.
Because of the poor prognosis of gallbladder carcinoma and
the possibility of a survival benet, as well as prolongation of
survival until recurrence, a radical surgical approach to these
advanced-stage gallbladder carcinomas is recommended by
many centers.
When gallbladder carcinoma is diagnosed during laparoscopy, the procedure should be converted to an open procedure, and the laparoscopic port sites should be resected
because tumor may recur at these sites secondary to iatrogenic
dissemination.131 Further surgical management then depends
on the tumor stage, as outlined earlier and in Figure 69-7.
When gallbladder carcinoma is diagnosed postoperatively,
further management depends on the tumor stage and the
Diagnosis of
gallbladder cancer

Staging

presence or absence of tumor at the margins of the surgical

specimen. The likelihood of nding residual disease at reexploration has been reported to be 50%, 61%, 85%, and 100%
for stage T1, T2, T3, and T4 tumors, respectively, in the initial
specimen.110 Neoadjuvant or adjuvant therapies do not provide
survival benets and are not recommended.55,110
The standard of care for patients with unresectable gallbladder carcinoma is chemotherapy with gemcitabine combined with cisplatin. This recommendation is based largely on
the ABC-02 trial (see earlier), which included 149 patients with
gallbladder carcinoma and showed an improvement in overall
survival of 3.6 months, similar to that for cholangiocarcinoma.67 Other chemotherapeutic agents and gemcitabinebased combination therapies (with oxaliplatin, 5-uorouracil
[5-FU], or capecitabine) and targeted agents (cetuximab, erlotinib, or bevacizumab) have been assessed in smaller studies
but have failed to show outcomes superior to those for the
combination of gemcitabine and cisplatin, which, therefore,
remains rst-line treatment in unresectable gallbladder
carcinoma. In general, gallbladder carcinoma is considered
radioresistant.

AMPULLARY CARCINOMA
Carcinomas of the ampulla of Vater belong to the family of
periampullary carcinomas. This family includes carcinomas of
the duodenum, ampulla of Vater, distal bile duct, and pancreas
(see Chapter 60). Ampullary carcinomas are the second most
common form of periampullary carcinoma (after pancreatic
head cancer). The distinction between the different forms is
important because ampullary carcinomas are often diagnosed
earlier than the others and therefore at a resectable stage, thus
resulting in a better prognosis.

Epidemiology
T2, T3, T4

T1

T1a

T1b

Re-exploration

Resectable

No further
treatment
if margins
are negative

M1

Radical
cholecystectomy

Unresectable

Palliative
treatment

FIGURE 69-7. Algorithm for the management of gallbladder carcinoma discovered intra- or postoperatively at laparoscopic cholecystectomy. In cases in which pathologic examination of the
cholecystectomy specimen identies a stage T1a tumor with
negative surgical margins, no further treatment is indicated. If the
tumor is found to be a stage T1b tumor or the margins of resection are positive for malignant tissue, reexploration for further
resection is indicated. Similarly, patients with gallbladder carcinoma found to be stage T2, T3, or T4 should undergo surgical
reexploration. If reexploration reveals resectable gallbladder carcinoma, radical cholecystectomy should be performed. If the
tumor is deemed unresectable, palliative management is indicated. When postoperative staging reveals metastatic spread,
palliative management is indicated. M, metastasis stage; T, tumor
stage. (Modied from Misra S, Chaturvedi A, Misra NC, Sharma
ID. Carcinoma of the gallbladder. Lancet Oncol 2003; 4:167-76.)

Ampullary carcinomas are rare, accounting for fewer than 1%

of all GI cancers and 4% to 8% of periampullary carcinomas.
The annual incidence has been estimated to be 0.6 per 100,000
population.132,133 Peak incidence is in the seventh decade of life.
There is a slight male predominance, with a male-to-female
ratio of 1.48 : 1.133 Racial heterogeneity has been observed; the
vast majority of patients are Caucasian, followed by patients
of Hispanic and Asian descent. African Americans have the
lowest incidence rates in the United States.132 The incidence of
ampullary carcinoma has increased by 0.9% annually in the
United States since the 1970s.134

Etiology
Although the etiology of ampullary carcinomas is unknown
in the majority of cases, several conditions have been associated with this malignancy, mostly in case reports or small
series. Familial adenomatous polyposis (FAP) is an important
risk factor for the development of ampullary carcinomas, with
a relative risk of 124 (see Chapter 126).135 Periampullary carcinoma is the second most common cause of death (after colon
cancer) in patients with FAP. Usually, periampullary carcinoma arises later than colorectal carcinoma in this patient
group but earlier in comparison with sporadic ampullary carcinomas.133 Screening for upper GI neoplasms (polyps or carcinoma) at regular intervals of 6 months to 4 years, depending
on the degree of duodenal polyposis, is therefore recommended in patients with FAP. Similarly, increased rates of
ampullary carcinoma have been described in patients with
Gardners syndrome, a variant of FAP (see Chapter 126).136
Lynch syndrome (hereditary nonpolyposis colorectal cancer)