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Biliary tract cancers. N Engl J Med

Article  in  New England Journal of Medicine · November 1999

DOI: 10.1056/NEJM199910283411807 · Source: PubMed

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 The New Eng land Jour nal of Medicine

Review Article

Medical Progress Although the numbers vary among countries and

regions, about two thirds of all cases of cholangio-
carcinoma are perihilar tumors, about one fourth are
B ILIARY T RACT C ANCERS distal extrahepatic tumors, and the remainder are in-
trahepatic.4 Except for embryonal rhabdomyosarco-
ma, the frequency of all types of biliary tract cancers
PIET C. DE GROEN, M.D., GREGORY J. GORES, M.D., increases with age. Gallbladder cancers are more fre-
NICHOLAS F. LARUSSO, M.D., quent in women,8 and cholangiocarcinomas are slight-
LEONARD L. GUNDERSON, M.D., ly more common in men.9 These sex differences are
AND DAVID M. NAGORNEY, M.D.
probably related to the higher incidence of gallstones
in women and of primary sclerosing cholangitis in
men. These are known risk factors for gallbladder can-

I
N the United States, an estimated 20,000 new
cer and cholangiocarcinoma, respectively.
cases of liver and biliary tract cancer are diag-
nosed annually.1 Biliary tract cancer is the sec- PATHOLOGICAL FEATURES
ond most common primary hepatobiliary cancer, af-
As with most tumors of the digestive system, the
ter hepatocellular cancer. Approximately 7500 new
large majority of primary tumors are carcinomas.10,11
cases of biliary tract cancer are diagnosed per year;
There are several histologic types, the most common
about 5000 of these are gallbladder cancer, and be-
of which are adenocarcinoma, papillary carcinoma,
tween 2000 and 3000 are bile-duct cancers.1 Biliary
and mucinous carcinoma. The histologic grade varies
tract cancers have traditionally been divided into can-
from well differentiated to undifferentiated. With the
cers of the gallbladder, the extrahepatic bile ducts,
exception of a rare cystadenocarcinoma, the tumors
and the ampulla of Vater, whereas intrahepatic bile-
consist of clusters of cells, sometimes surrounded by
duct cancers have been classified as primary liver can-
desmoplastic stroma (Fig. 2A). The desmoplastic re-
cers.2 The term “cholangiocarcinoma” was originally
action of a cholangiocarcinoma can be so extensive
intended to refer only to primary tumors of the in-
that the specimen consists mainly of fibrous tissue with
trahepatic bile ducts and was not used for tumors
sporadic clumps of malignant cells. This feature, espe-
of the extrahepatic bile ducts.3 Lately, however, the
cially in patients with cholangitis, intraductal gall-
term has been used to include intrahepatic, peri-
stones, or bile-duct stents, makes it very difficult to
hilar, and distal extrahepatic tumors of the bile ducts.4
distinguish between reactive tissue and well-differen-
Perihilar tumors involving the bifurcation of the
tiated cholangiocarcinoma. Because normal and malig-
hepatic duct are also called Klatskin tumors, from
nant bile-duct epithelial cells are not known to express
Klatskin’s original description in 1965.5 In this re-
a protein unique to bile-duct tissue, there is no path-
view, the term “cholangiocarcinoma” is used for pri-
ognomonic immunohistochemical test to confirm the
mary tumors of the bile ducts, including intrahepatic,
cell type of origin. However, several types of immu-
perihilar, and distal extrahepatic tumors (Fig. 1).
nohistochemical staining support the diagnosis of
The perihilar bile-duct tumors were further classi-
malignant biliary tract tissue. The most frequently
fied by Bismuth et al. as tumors below the conflu-
used stains are immunohistochemical stains for cyto-
ence of the left and right hepatic ducts (type I),
keratins, carcinoembryonic antigen, and mucins (Fig.
tumors reaching the confluence (type II), tumors
2B and 2C). Other tumor types, which occur in less
occluding the common hepatic duct and either the
than 5 percent of cases, include squamous-cell car-
right or the left hepatic duct (types IIIa and IIIb, re-
cinoma, small-cell carcinoma, and mesenchymal tu-
spectively), and tumors that are multicentric or that
mors. In patients with the acquired immunodeficiency
involve the confluence and both the right and left
syndrome (AIDS), Kaposi’s sarcoma and lymphoma
hepatic ducts (type IV).6 Even more detailed classi-
of the biliary tract have been reported.12,13 Finally,
fications have been proposed, but they are not used
many other types of tumor can obstruct the biliary
in daily practice.7 Most cholangiocarcinomas involve
tree by direct extension (for example, in the case of
the perihilar and distal extrahepatic bile ducts.
tumors of the pancreas, duodenum, stomach, or co-
lon), metastasis (for example, tumors of the ovary,
breast, or colon), or lymph-node involvement (for ex-
From the Mayo Clinic, Rochester, Minn. Address reprint requests to Dr. ample, lymphoma). These tumors will not be dis-
de Groen at the Division of Gastroenterology and Hepatology, Mayo Clinic,
200 First St. SW, Rochester, MN 55905. cussed in this review.
©1999, Massachusetts Medical Society. The stage of cancers of the biliary tract is deter-

1368 · Octo b er 2 8 , 19 9 9
 MED IC A L PROGR ES S

A
Liver

Common
hepatic duct
Intrahepatic

Gallbladder
Perihilar

Common
bile duct Distal
extrahepatic
A
Ampulla
of Vater

Duodenum

B Type I Type II

Type IIIa Type IIIb

Type IV

Figure 2. Cholangiocarcinoma.
Tumor cells are shown after staining with hematoxylin and
eosin (Panel A, ¬62), carcinoembryonic antigen (Panel B, ¬62),
and MUC-1 (Panel C, ¬125). There is extensive desmoplastic
stroma surrounding the tubules of the cholangiocarcinoma cells.
Figure 1. Classification of Cancers of the Human Biliary Tract. The specimens in Panels B and C are from the same patient.
Panel A shows the overall classification of biliary tract cancers.
Panel B shows the Bismuth classification of perihilar cholangio-
carcinomas. Yellow areas represent tumor, and green areas
normal bile duct.

Vol ume 341 Numb e r 18 · 1369

 The New Eng land Jour nal of Medicine

mined according to the tumor–node–metastasis sys- within 2 years after the diagnosis of primary scleros-
tem of classification.14 Because the staging is slightly ing cholangitis.27,29 Patients who have ulcerative colitis
different for each type of biliary tract cancer, we give in the absence of symptomatic primary sclerosing cho-
only a general description of the stages. Biliary tract langitis or who have long-standing intraductal gall-
cancers are classified from stage 0 to stage IV. Stage stone disease also have an increased risk.27,30 Other,
0 is carcinoma in situ; this stage is not defined for rarer conditions associated with the development of
intrahepatic cholangiocarcinoma. In stage I, tumor cholangiocarcinoma include bile-duct adenoma, mul-
invasion is limited to the mucosa, muscle layer, or tiple biliary papillomatosis, choledochal cysts, Caroli’s
ampulla. In stage II, local invasion of tumor is seen. disease (cystic dilatation of intrahepatic bile ducts),
In stage III, tumor invasion is similar to that in stage and exposure to the radiopaque medium thorium
I or II, but metastasis into regional and hepato- dioxide (Thorotrast).30 In Southeast Asia, infestation
duodenal lymph nodes or invasion of adjacent tis- with the parasites Opisthorchis viverrini (in Thailand,
sues has occurred. Stage IV cancer is characterized Laos, and Malaysia)31 or Clonorchis sinensis (in Japan,
by extensive invasion of the liver; invasion of adja- Korea, and Vietnam)32 is associated with an increase
cent structures or organs; metastases in peripancre- by a factor of 25 to 50 in the risk of cholangiocar-
atic, periduodenal, periportal, celiac, or mesenteric cinoma. Case–control studies have shown an increased
lymph nodes; and distant metastases. risk associated with smoking.33,34 However, despite all
these known risk factors, many cases of cholangiocar-
RISK FACTORS cinoma occur in patients without obvious risk factors.
Specific risk factors for the development of hepa- Adenomas of the ampulla of Vater, especially when
tobiliary cancer have been associated with different they are villous, are known to be premalignant le-
parts of the biliary tree. Gallbladder cancer is more sions. Adenomas are frequently seen in patients with
frequent in patients with gallstones,15 especially if the familial adenomatous polyposis,35 who have a risk of
gallstones are symptomatic16 and large.17 Other fac- ampullary adenocarcinoma that is 100 times that in
tors associated with gallbladder cancer include female the normal population.36 Other possible, but not well-
sex, obesity, and high carbohydrate intake, all of which established, risk factors include cholecystectomy, en-
are also associated with gallstone disease.16 However, doscopic sphincterotomy, and use of tobacco.33,37,38
the increase in the risk of gallbladder cancer in patients Finally, AIDS has been associated with cancers
who have cholelithiasis but no symptoms or other risk throughout the entire biliary tract, including the
factors is so low that prophylactic resection of the ampulla of Vater.12,13,39
gallbladder is not recommended. For persons over 50
years of age, the rate of gallbladder cancer is about MOLECULAR ASPECTS
0.02 percent per year.18 Bacterial infection of bile, with Conversion from normal to malignant bile-duct
or without gallstone disease, occurs in up to 80 per- tissue probably requires a number of successive ge-
cent of patients with gallbladder cancer.19,20 Studies nomic mutations similar to the sequence of events
from Chile, Bolivia, and India suggest that the com- proposed for other gastrointestinal cancers, although
bination of chronic infection with Salmonella typhi and our knowledge of biliary tract cancers is less exten-
cholelithiasis is strongly associated with gallbladder sive than that of the more common gastrointestinal
cancer.21,22 Polyps, especially when they are more than cancers. A variety of mutations in oncogenes, as well
1 cm in diameter, and calcification of the gallbladder as tumor-suppressor genes, have been described in
wall (porcelain gallbladder) are other predisposing specimens of biliary tract tumors. These include mu-
factors for cancer.23,24 Finally, anomalous pancrea- tations in the oncogenes K-ras, c-myc, c-neu, c-erb-b2,
ticobiliary ductal junction, a rare anatomical anom- and c-met and the tumor-suppressor genes p53 and
aly sometimes associated with a choledochal cyst and bcl-2.40-43 These mutations may lead to detectable
found mostly among Asians, is associated with a phenotypic changes; for instance, biliary epithelial
markedly increased risk of gallbladder cancer.25 In cells switch from expressing MUC-1 apomucin be-
patients with this condition, prophylactic cholecys- fore birth to MUC-3 after birth.44 Malignant trans-
tectomy with cyst excision is recommended. formation can reverse this process, and as mentioned
Cholangiocarcinoma, both intrahepatic and extra- before, many cholangiocarcinomas show staining with
hepatic, is a well-known complication of primary scle- antibody to MUC-1. Similarly, core mucin carbohy-
rosing cholangitis. Although lifetime risks in excess drate Tn and sialyl-Tn antigens were expressed in
of 30 percent have been reported among patients with many intrahepatic bile-duct cancers.44,45 However, as
primary sclerosing cholangitis, most studies mention with other tissue types, mutations and phenotypic
lifetime risks of about 10 percent.26-28 The time from changes are also seen under nonmalignant conditions,
the diagnosis of primary sclerosing cholangitis to precluding their routine use in clinical practice. Al-
the development of cholangiocarcinoma ranges from though there is much speculation regarding the fac-
1 year to more than 25 years, although at least one tors that induce the various mutations, such as chronic
third of cases of cholangiocarcinoma are diagnosed inflammation, ethnic background, diet, and exposure

1370 · Octo b er 2 8 , 19 9 9
 MED IC A L PROGR ES S

to carcinogens, little or nothing is known about how

these factors actually cause biliary tract cancer. TABLE 1. POTENTIAL TUMOR MARKERS IN GALLBLADDER CANCER
AND CHOLANGIOCARCINOMA .
DIAGNOSIS
The most common presenting symptoms of bil- MARKER REFERENCE
iary tract cancer are caused by bile-duct obstruction In bile
and include jaundice, clay-colored stools, cola-colored Tumor antigens or products
urine, and pruritus.7,46 These symptoms tend to oc- Carcinoembryonic antigen Ker et al.48
CA 19-9 Ker et al.49
cur early if the tumor is located in the common CA 125 Ker et al.49
hepatic duct, the common bile duct, or the ampulla Sialyl-Tn antigen Sasaki et al.50
of Vater. They develop later in perihilar disease and, Fibronectin Körner et al.51
Oncogene
when present, are often markers of advanced disease K-ras Rijken et al.,42
in cancer of the gallbladder and intrahepatic cholan- Voravud et al.43
Tumor-suppressor gene
giocarcinoma. Pain in the right upper quadrant is p53 Suto et al.40
the most frequent presenting symptom in gallblad- Metabolic product
der cancer but not in cholangiocarcinoma.7 In gen- Lactate Nishijima et al.52
In serum
eral, pain, fatigue, malaise, and weight loss occur in Tumor antigens or products
advanced disease. The combination of acute right- Carcinoembryonic antigen Kuusela et al.53
upper-quadrant pain, fever, and chills, in association CA 19-9 Kuusela et al.,53 Su et al.54
CA 50 Kuusela et al.53
with cholestasis, strongly suggests cholangitis. Chol- CA 125 Su et al.54
ecystitis in elderly patients is sometimes the first man- CA 195 Bhargava et al.55
CA 242 Kuusela et al.53
ifestation of gallbladder cancer.47 Occasionally, pan- DU-PAN-2 Maeda et al.56
creatitis is the first manifestation of a periampullary Cytokeratin 19 fragment Kashihara et al.57
tumor. The physical examination may reveal jaundice, Protein induced by the absence of Nakao et al.58
vitamin K or antagonist II (PIVKA-II)
right-upper-quadrant pain, hepatomegaly, and a pal- Cytokine
pable gallbladder or mass, depending on the location Interleukin-6 Goydos et al.59
Proteases
and stage of the tumor. Trypsinogen-2 Hedstrom et al.60
Abnormal laboratory-test results in biliary tract can- Trypsin-2–a1-antitrypsin complex Hedstrom et al.60
cer can be divided into those due to interference with Peptide
Pancreatic polypeptide Bruckner et al.61
normal physiologic processes, resulting from inhibi-
tion of normal bile flow or tumor invasion, and those
due to the secretion of abnormal products. Cholesta-
sis and cholecystitis due to obstruction of bile flow
typically result in moderate-to-marked increases in none seem to be as useful as CA 19-9.54 We also use
serum levels of alkaline phosphatase, bilirubin, g-glu- serum CA 19-9 levels to assess the effect of treat-
tamyltransferase, and bile acids, whereas aminotrans- ment and to detect recurrence of the disease.
ferase levels are only mildly elevated or normal. The first diagnostic imaging procedure in most pa-
Prolonged obstruction of the common hepatic or tients with cholestasis or right-upper-quadrant pain
common bile duct may lead to deficiency of fat-sol- is ultrasonography of the liver and gallbladder.65 Gall-
uble vitamins and increased prothrombin time. Ma- bladder cancers and intrahepatic cholangiocarcinoma
lignant transformation may result in the secretion of may be detected as mass lesions. The absence of mo-
abnormal products into the bile or serum. Indeed, a bile filling defects within the gallbladder that atten-
large number of potential markers of biliary tract uate the sonographic beam with “shadow” essentially
cancers have been identified. Many markers, however, excludes the possibility of cholelithiasis. Perihilar, ex-
are not specific and may also be present under non- trahepatic, and periampullary cancers may not be de-
malignant conditions (Table 1).59,62 Of these, cancer tected by ultrasonography, especially when they are
antigen (CA) 19-9 is currently widely used, in partic- small. Instead, indirect signs may point toward these
ular for detecting cholangiocarcinoma in patients with diagnoses. The most common indirect sign is ductal
primary sclerosing cholangitis (Fig. 3).63,64 Serum CA dilatation throughout the obstructed liver segments;
19-9 levels greater than 100 U per milliliter (the nor- an abrupt change in ductal diameter may indicate
mal level is less than 40 U per milliliter) have been the exact location of the tumor. Color Doppler im-
reported to have a sensitivity of 89 percent and a spec- aging can detect compression, encasement, or throm-
ificity of 86 percent for the detection of cholangio- bosis of the portal vein as well as encasement or
carcinoma in these patients.63 A marker consisting of occlusion of the hepatic artery by tumor.66 The sensi-
CA 19-9 in combination with carcinoembryonic an- tivity and specificity of ultrasonography vary with
tigen (according to the formula CA 19-9+ [carcino- the type of tumor, the quality of the equipment, and
embryonic antigen¬40]) had an accuracy of 86 per- the experience of the operator. Under optimal condi-
cent.64 Other serum markers have been studied, but tions, gallbladder cancers are detected in at least 50

Vol ume 341 Numb e r 18 · 1371

 The New Eng land Jour nal of Medicine

1800

1600 ERC and biopsy

1400
CA 19-9 (U/ml)

1200

1000

800 CT and ERC

600 Ultrasonography

400

200

0
A

8
Bilirubin
(mg/dl)

6
4
2
0
8
8
6

/9
/9
/9

/9

/9

24
24
/1

30

27
12

7/
2/
4/

9/

Date
Figure 3. CA 19-9 and Bilirubin Levels in a 75-Year-Old Man with
Primary Sclerosing Cholangitis since 1972 and Cirrhosis.
CA 19-9 levels gradually increased, although bilirubin levels
remained near normal, and ultrasonography and computed to-
mography (CT) did not reveal a focal abnormality. On endoscop-
ic retrograde cholangiography (ERC), strictures and dilatations
of bile ducts typical of primary sclerosing cholangitis were seen,
with hilar strictures suggesting cholangiocarcinoma. Brush spec- B
imens did not show atypical cells, but mild cytologic atypia was
evident in other biopsy specimens. Repeated endoscopic retro-
grade cholangiography with biopsy five months later revealed
a single focus of well-differentiated, invasive adenocarcinoma.

percent of cases, and detection rates as high as 86 per-

cent have been reported for cholangiocarcinoma.67,68
Computed tomographic (CT) scanning may show
an intraluminal gallbladder mass, with or without di-
rect invasion of the liver or other adjacent tissues (Fig.
4A).69 Intrahepatic mass lesions (Fig. 4B) and dilat-
ed intrahepatic ducts (Fig. 4C) are easily detected,
but visualization of perihilar tumors or tumors in-
volving the portal venous or arterial system is best
achieved by intravenous bolus-enhanced spiral or hel- C
ical CT scanning.70 Dilatation of the intrahepatic bile
Figure 4. Computed Tomographic Scans of Patients with Gall-
ducts in a single, small hepatic lobe with hypertrophy bladder Cancer and Intrahepatic and Hilar Cholangiocarcinoma.
of the contralateral lobe suggests the atrophy–hyper- Panel A shows a large gallbladder cancer (arrow) filling part of
trophy complex, as seen with tumors chronically ob- the distended gallbladder and invading the adjoining intestine.
structing a single lobe and invading the ipsilateral Panel B shows a huge intrahepatic cholangiocarcinoma (arrow)
portal vein.71 Bilobate dilated intrahepatic ducts and limited to the right hepatic lobe. Panel C shows a hilar cholangio-
carcinoma causing marked dilatation of the bile ducts in the lat-
a normal or collapsed gallbladder and common bile eral segments of the left lobe. The left medial segment is atro-
duct suggest a perihilar tumor. A distended gallblad- phied (arrow). The bile ducts in the right hepatic lobe are also
der without dilated intrahepatic or extrahepatic ducts dilated.

1372 · Oc to b er 2 8 , 19 9 9
 MED IC A L PROGR ES S

is seen in patients with cystic duct stones and tu-

mors. On the other hand, a distended gallbladder with
dilated intrahepatic and extrahepatic ducts is typical
of distal extrahepatic ductal cancers, cancers of the
ampulla of Vater, intraductal gallstones, or pancreatic
cancers. Tumor emboli from hepatocellular cancer, RA
metastatic colorectal cancer, or intrahepatic cholan-
giocarcinoma are an unusual cause of perihilar or dis-
tal extrahepatic bile-duct obstruction.72 Unlike ultra- L
sonography, CT may also show the peripancreatic,
periduodenal, periportal, celiac, and mesenteric lymph
nodes. Both ultrasonography and CT permit guided
fine-needle aspiration or biopsy of suspicious lesions. RP
Magnetic resonance imaging (MRI) permits ex-
cellent visualization of hepatic parenchymal abnor-
malities, as well as the visualization of the biliary tree
and vascular structures. MRI with the use of ferrous G
oxide and gadolinium yields information similar to
that yielded by CT, cholangiography, and angiogra-
phy combined.73,74 Because MRI is noninvasive and
does not involve exposure to radiation, it may replace
CT and angiography for the preoperative assessment
of biliary tract cancers.
Without doubt, cholangiography is currently the
most important radiologic procedure for assessing
the resectability of a tumor. Both percutaneous cho-
langiography and endoscopic retrograde cholangiog-
raphy are performed; the choice of procedure de-
pends on the suspected location of the tumor and
the experience of the operators. In general, more
proximal and sclerotic tumors are best assessed by
Figure 5. Cholangiogram of a Patient with Cholangiocarcinoma.
percutaneous transhepatic cholangiography (Fig. 5),
RA denotes the right anterior ductal system, RP the right pos-
whereas distal extrahepatic and simple perihilar lesions terior ductal system, L the left ductal system, and G the gall-
are amenable to endoscopic assessment. Periampul- bladder. The broad, open arrow points to part of the duct that
lary tumors can be directly visualized and biopsies is narrowed by tumor; the broad, solid arrow to the track of the
can be performed with a side-viewing endoscope. percutaneous needle used to inject contrast material; the ar-
rowhead to the cystic duct; and the curved arrow to the com-
Both the distal and the proximal extent of tumor
mon hepatic duct.
growth must be clearly visualized to help the sur-
geon decide whether an attempt at curative resection
is feasible. However, diffuse abnormalities of the bil-
iary system, such as those seen in primary sclerosing
cholangitis, sometimes make it impossible to delin- from ductal shave biopsies with an atherectomy cath-
eate a tumor exactly. eter and percutaneous biopsies at the location of the
Because many patients with gallbladder carcinoma suspected tumor immediately adjacent to a previously
present with obstructive jaundice, cholangiography placed biliary stent.77 Placement of percutaneous or
is also frequently used in the preoperative assess- endoscopic stents relieves symptoms, improves hepat-
ment of this tumor; typically, a long stricture of the ic function, and allows palpation of the ductal struc-
common hepatic duct is found. Once access to the tures at the time of exploration.
biliary tree has been achieved, bile samples or brush Angiography accurately documents vascular en-
cytologic or biopsy specimens can be obtained. Bile casement and thrombosis of the portal vein and hepat-
samples, obtained through a percutaneous stent, con- ic artery, but in most cases it is not necessary before
tain cancerous cells in 30 to 40 percent of cases of surgery. When combined with cholangiography, it
cholangiocarcinoma.75,76 The use of brush biopsy and correctly predicts resectability in the majority of cas-
cytologic examination may increase the yield to 40 es.78,79 However, as mentioned before, MRI may re-
to 70 percent. Unfortunately, even percutaneous or place angiography for the assessment of vascular en-
endoscopic biopsy not infrequently yields nondiag- casement and patency.
nostic tissue because of the desmoplastic nature of Several new and promising imaging techniques have
the lesion. The highest diagnostic yield may come recently become available. Endoscopic ultrasonogra-

Vol ume 341 Numb e r 18 · 1373

 The New Eng land Jour nal of Medicine

phy can be used to visualize the distal extrahepatic bil- tively treated with laparoscopic cholecystectomy. Al-
iary tree, the gallbladder, and the regional lymph nodes though curative resection of stage II disease may
in great detail.80 The use of an endoscope equipped also be achieved by laparoscopic cholecystectomy, the
with linear ultrasonography allows ultrasound-guided survival rates are higher when more extensive, open
fine-needle aspiration of suspected tumors and ab- resections are performed.90 For most stage II, III,
normal or enlarged lymph nodes.81 Positron-emission and IV gallbladder cancers, extended or radical chol-
tomography (PET) permits the metabolism of bile- ecystectomy is preferred.91 In addition to the gall-
duct epithelial cells to be assessed in vivo by means of bladder, the adjacent liver tissue and regional lymph
a glucose analogue, [18F]fluoro-2-deoxy-D-glucose.82,83 nodes are removed. Depending on the extent of liver
Cholangiocarcinoma cells have a high glucose uptake. invasion, subsegmental, bisegmental, lobar, or extend-
Both glucose and [18F]fluoro-2-deoxy-D-glucose are ed lobar resection is performed. Japanese investiga-
phosphorylated, but [18F]fluoro-2-deoxy-D-glucose is tors found a five-year survival rate of 75 to 80 per-
not further metabolized. As a result, cholangiocarci- cent in patients with disease limited to the mucosa,
noma cells accumulate [18F]fluoro-2-deoxy-D-glucose, muscularis, or subserosa who were treated by ex-
causing “hot spots” on scanning. In addition, hepato- tended cholecystectomy.92 Even more aggressive sur-
cytes have high glucose-6-phosphatase activity and rap- gery has been performed in patients with extension of
idly turn over [18F]fluoro-2-deoxy-D-glucose, thereby tumor into the duodenum, pancreas, colon, or kid-
further increasing the signal-to-background ratio. Sev- ney fossa.93 As expected, mortality and morbidity have
eral small studies have documented the ability of PET been high, and the outcome in general has been dis-
to detect cholangiocarcinomas as small as 1 cm in di- appointing. The overall survival, except for patients
ameter.82,83 Other, less frequently used new diagnos- with stage 0 or I tumors, is dismal. Most patients
tic methods include intraductal ultrasonography,84 present with advanced disease, and the combined five-
endoscopic or percutaneous flexible cholangioscopy,85 year survival for all stages of gallbladder cancer is be-
and radiolabeled antibody or ligand imaging.86,87 tween 5 and 10 percent.
Cancers of the gallbladder and of the perihilar and Intrahepatic cholangiocarcinoma is generally treat-
distal extrahepatic bile ducts may spread directly into ed by hepatic resection alone.94,95 The surgical treat-
adjacent organs or the abdominal cavity, where they ment of perihilar cholangiocarcinoma depends on
can be detected by ultrasonography, CT, MRI, or the Bismuth class.6 Most authors report that about
endoscopic ultrasonography. The exact extent of in- one third of patients can undergo curative resection,
vasion, however, may be difficult to discern. In gall- but some suggest that up to two thirds of patients
bladder cancer, metastatic disease is rather common should undergo resection with curative intent.4 En
and occurs early. In perihilar and distal extrahepatic bloc resection of the extrahepatic bile ducts and gall-
bile-duct cancers, distant metastases are relatively in- bladder, regional lymphadenectomy, and Roux-en-Y
frequent and occur late in the course of the disease. hepaticojejunostomy are recommended for type I and
The lungs and bones are most commonly involved. II tumors, and that treatment plus hepatic lobecto-
The metastases can be detected by chest radiography, my is recommended for type III tumors.88,96,97 The
CT, or bone scanning. intent is to achieve a tumor-free proximal margin of
at least 5 mm.98 Because type II and III tumors often
TREATMENT AND SURVIVAL
involve the ducts of the caudate lobe, caudate lobec-
Surgery tomy is recommended to improve local control and
At present, only surgical excision of all detectable survival for patients with type II or III tumors.88,99,100
tumor is associated with improvement in five-year In distal extrahepatic tumors and cancers of the am-
survival.4,8,9,46 Multiple factors related to both the pulla of Vater, pancreatoduodenectomy is the thera-
patient and the tumor need to be evaluated when as- py of choice. Commonly, a pylorus-preserving Whip-
sessing resectability.7 Poor performance status, major ple procedure is performed. Survival is directly related
cardiopulmonary disease, and preexisting cirrhosis are to the stage of disease. The median survival for pa-
the most common patient-related factors precluding tients with intrahepatic cholangiocarcinoma without
surgical exploration. Poor nutritional status, sepsis, involvement of the hilum varies among centers from
and severe cholestasis also predict a poor outcome, but 18 to 30 months. The median survival for patients
these factors can sometimes be reversed preoper- with perihilar cholangiocarcinoma is slightly less, vary-
atively. Distant metastases, extensive regional lym- ing from 12 to 24 months.96,101 The five-year survival
phadenopathy, and regional vascular encasement or for both groups of patients varies between 10 percent
invasion preclude resection. Although laparoscopic and 45 percent, with the best results reported from
ultrasonography in some cases may alter either the Japan.88,100,102 Finally, five-year survival rates of 15 to
diagnosis or the staging of the tumor while obviat- 25 percent in patients with distal extrahepatic cho-
ing the need for open laparotomy,88,89 its value is not langiocarcinoma and of 50 to 60 percent in patients
fully known. with periampullary cancers have been reported.103-105
Stage 0 and stage I gallbladder cancers are effec- Patients with unresectable intrahepatic or perihi-

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lar cholangiocarcinoma in the absence of extrahepat- life in patients with biliary tract cancers. A large
ic disease are potentially treatable with total resection number of agents, including fluorouracil, mitomycin,
of the liver, bile ducts, and hilar lymph nodes, followed methotrexate, etoposide, doxorubicin, 1-(2-chloro-
by orthotopic liver transplantation.106,107 The results of ethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and cis-
resection of cholangiocarcinoma in patients with in- platin, have been tested as single or combination
trahepatic or perihilar cholangiocarcinoma as a com- therapies without appreciable effects. Partial responses
plication of primary sclerosing cholangitis are dismal.29 lasting from weeks to several months have been ob-
These patients can also potentially be treated by or- served in approximately 10 to 20 percent of cases.119
thotopic liver transplantation. However, the early re-
sults of orthotopic liver transplantation in both groups Other Palliative Treatments
of patients have been disappointing, with rapid recur- In most patients who are not candidates for sur-
rence of disease.108,109 At the Mayo Clinic, patients un- gery, endoscopically or percutaneously placed plastic
dergoing orthotopic liver transplantation for cholan- or metal stents relieve the symptoms associated with
giocarcinoma are selected according to very strict cholestasis.120 Plastic stents tend to become occlud-
criteria and undergo preoperative external-beam and ed and require replacement approximately every three
internal transcatheter radiation, continuous intrave- months. Metal stents tend to stay open longer be-
nous chemotherapy, and pretransplantation explor- cause of their larger diameter. They rarely migrate
ative laparotomy. According to preliminary data, all and are currently widely used.121 According to a re-
patients treated so far have had prolonged tumor- cent report, the use of a hematoporphyrin derivative
free survival. as a sensitizer, followed two days later by intralumi-
Palliative surgery is used selectively.96,110 Removal nal photoactivation, resulted in prolonged biliary de-
of the gallbladder may prevent acute cholecystitis in compression and an improved quality of life.122 Pain
patients with gallbladder cancer. In all forms of bil- is managed by oral and percutaneous narcotics and,
iary tract cancer, a gastrojejunal bypass for the treat- if needed, by a celiac-plexus block. Survival is related
ment or prevention of obstruction of the gastric to the stage of the disease. The median survival var-
outlet is selectively indicated; intraoperatively, a neu- ies from 6 to 12 months, with most centers report-
rolytic celiac-plexus block can be performed for pain ing no patients surviving at 5 years.46,96,104,110
control. Some centers have reported good palliation
and quality of life after a segment III or V hepaticoje- FUTURE DIRECTIONS
junostomy.111,112 Finally, adequate relief of cholestasis Major improvement in the survival of patients with
due to distal extrahepatic tumors can be obtained cancers of the biliary tree will probably not result
with choledochojejunostomy or hepaticojejunostomy. from more aggressive or advanced surgical techniques
or oncologic radiation therapy. Instead, efforts should
Radiation be directed at prevention, early detection, and novel
Biliary tract cancers are difficult to control locally treatments derived from basic research. The universal
by external-beam radiation therapy alone. However, benefits of smoking cessation and weight reduction
external irradiation, alone or in combination with are obvious. Populations at risk — that is, patients
fluorouracil, may relieve pain and contribute to bil- with primary sclerosing cholangitis, intraductal stones,
iary decompression. cystic diseases of the biliary system, cholelithiasis
When external irradiation is used in combination combined with S. typhi infection, liver flukes, or fa-
with total resection in patients with microscopically milial adenomatosis polyposis — need to be identi-
involved margins, or in combination with fluorour- fied so they can be offered preventive strategies and
acil and supplemental transcatheter brachytherapy, prophylactic or early treatment.123 For instance, pa-
survival appears to be prolonged, and in a few cases tients with primary sclerosing cholangitis who are
long-term survival has been reported.113-115 The me- found to have cellular atypia on initial brush cyto-
dian survival increases from 6 to 8 months among logic examination may benefit from programs of an-
patients treated with surgery or palliative stent place- nual surveillance consisting of a serum CA 19-9
ment and chemotherapy to 12 to 19 months among measurement and endoscopic retrograde cholangi-
those who receive similar treatment combined with ography. The use of brush cytologic examination or
external-beam irradiation.114-116 Escalation of the ra- biopsy would be analogous to current surveillance
diation dose may increase survival.113,115 Other inves- strategies for inflammatory bowel diseases.124
tigators have not found a significant survival benefit There is a need for new, cost-effective screening
resulting from the addition of irradiation to surgical methods, including simple assays for tumor markers in
resection or stenting.117,118 the serum, bile,125 or stool.126 A noninvasive radiolog-
ic technique that can detect disease at a curable stage
Chemotherapy may already exist, if the early data from studies of PET
Preoperative or postoperative chemotherapy does scanning are confirmed in larger series. Several prom-
not significantly improve survival or the quality of ising chemopreventive agents, currently under inves-

Vol ume 341 Numb e r 18 · 1375

 The New Eng land Jour nal of Medicine

tigation for other types of cancer, may also be bene- 22. Dutta U, Garg PK, Kumar R, Tandon RK. Chronic salmonella typhi
carrier state and cholelithiasis: cofactors in the pathogenesis of carcinoma
ficial to patients with primary sclerosing cholangitis. of the gallbladder. Digestion 1998;59:Suppl 3:576. abstract.
For patients with nonresectable disease, new drugs 23. Chijiiwa K, Tanaka M. Polypoid lesion of the gallbladder: indications
that selectively target malignantly transformed cells of carcinoma and outcome after surgery for malignant polypoid lesion. Int
Surg 1994;79:106-9.
without damaging normal tissue are required. In- 24. Polk HC Jr. Carcinoma and the calcified gall bladder. Gastroenterolo-
deed, several promising novel therapeutic agents, in- gy 1966;50:582-5.
25. Chijiiwa K, Kimura H, Tanaka M. Malignant potential of the gallblad-
cluding farnesyl transferase and angiogenesis inhibi- der in patients with anomalous pancreaticobiliary ductal junction: the dif-
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26. Kornfeld D, Ekbom A, Ihre T. Survival and risk of cholangiocarcino-
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netic repair of the mutations responsible for the ma- 1996;38:610-5.
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55.
Supported by the Mayo Foundation. 29. Rosen CB, Nagorney DM, Wiesner RH, Coffey RJ Jr, LaRusso NF.
Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann
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