mesenteric artery nodes. Nodal disease in the porta hepatis often causes common bile duct (CBD)

obstruction and resultant jaundice, which is the first clinical symptom in 30% of patients. Jaundice may

also be caused by tumors arising in the infundibulum, which may spread directly to the cystic duct and

common hepatic duct. Although peritoneal metastases are frequent, distant extraperitoneal metastases

are not.

Limited information exists regarding the genetic changes in gallbladder cancer. Recently reported

gene abnormalities associated with gallbladder cancer include p53, K-ras, CDKN2 (9p21), FGFR, and PI3

kinase pathway aberrations.16–20 The finding that patients with an anomalous pancreaticobiliary

junction have a greater frequency of K-ras mutations has led investigators to believe that reflux of

pancreatic enzymes into the biliary tree may contribute to the development of cancer.16 Because of our

limited knowledge of the sequence of molecular changes, there are no known detectors of early disease

or of risk assessment. Clearly, this is an area that needs improvement, particularly in endemic areas.

The American Joint Committee on Cancer’s (AJCC) seventh edition of its tumor, node, metastasis

(TNM) staging system (Table 63-1) reflects prognostic characteristics of tumor depth, regional nodal

disease, and distant spread. The gallbladder differs histologically from the rest of the gastrointestinal

tract in that it lacks a muscularis mucosa and submucosa. The gallbladder wall is composed of (a) a

single layer of columnar cells, the mucosa, and lamina propria; (b) a fibromuscular layer; (c) a

perimuscular, subserosal layer containing lymphatics and neurovascular structures; and (d) a serosal

surface, except where the gallbladder is embedded in the liver. Because lymphatics are present in the

subserosal layer only, tumors invading less than the full thickness of the muscular layer have minimal

risk of nodal spread. Thus, disease invading into, but not through, the muscular layer of the gallbladder

is T1b disease (stage I), whereas invasion into the perimuscular connective tissue is T2 (stage II). Stage

III disease includes tumors that have perforated the serosa or have directly invaded the liver or other

surrounding structures (T3), which are clearly more advanced but still potentially resectable. Tumors

that invade the main portal vein, hepatic artery, or two or more extrahepatic organs/structures are

classified as T4 (stage IVA) and are typically unresectable. Lymph node metastasis to regional,

periportal nodes are N1 whereas those to more distant nodes outside of what would be included in a

standard resection (celiac, periaortic, and superior mesenteric nodes) are N2. N1 nodal metastasis is

classified as stage IIIB and N2 as stage IVB. In line with other pancreaticobiliary malignancies, the stage

III grouping refers to locally advanced disease and stage IV indicates metastatic disease.

Clinical Findings and Diagnosis

Most patients are found to have gallbladder cancer during workup or treatment of cholelithiasis or

choledocholithiasis. In patients with symptoms, abdominal pain consistent with biliary colic or acute

cholecystitis is most common. Patients also present with jaundice, weight loss, anorexia, or an increase

in abdominal girth secondary to ascites. Physical findings may include right upper quadrant tenderness

or a palpable mass, hepatomegaly, and ascites. Laboratory investigation, if abnormal, is most often

consistent with biliary obstruction. Because of its nonspecific presentation and the lack of reliable

screening tests, gallbladder cancer is not diagnosed preoperatively in more than half the cases.

Imaging evaluation often reveals a thickened gallbladder wall or a mass within or replacing the

gallbladder on ultrasound examination. Because polyps, asymmetric wall thickening from cholecystitis

(especially xanthogranulomatous type), and carcinoma can have an echogenicity similar to the

gallbladder wall, these lesions are often difficult to distinguish. This is even more difficult when

inflammation is present from gallstones. At times, ultrasound can visualize invasion of the liver,

adjacent adenopathy, and a dilated biliary tree. The ability of ultrasound to differentiate benign from

neoplastic disease is enhanced using endoscopic ultrasound, and may be more specific than computed

tomography (CT) or magnetic resonance imaging (MRI).21–23

A dynamic contrast-enhanced CT scan may identify a gallbladder mass or invasion into the liver

parenchyma or adjacent organs. The classic finding in a patient with gallbladder cancer is asymmetric

thickening of the gallbladder wall. Staging of gallbladder carcinoma using CT, however, is limited by

poor sensitivity in identifying nodal spread.24

In patients who are jaundiced, direct cholangiography may be useful to delineate the extent of biliary

involvement as well as to palliate symptoms of biliary obstruction. A mid–bile duct obstruction not

caused by gallstones is gallbladder cancer until proved otherwise (Fig. 63-2). More recently, with

improvements in MRI technology, diffusion-weighted imaging and magnetic resonance

cholangiopancreatography (MRCP) have evolved into a single, noninvasive imaging modality that

allows complete assessment of biliary, vascular, hepatic parenchymal, and nodal involvement, as well as

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involvement of adjacent organs (Fig. 63-3).25–27

STAGING

Table 63-1 American Joint Committee on Cancer, 7th Edition, Staging System for

Gallbladder Carcinoma

In patients who present with incidentally discovered gallbladder cancer following cholecystectomy,

staging should be performed with high-quality CT or MRI of the chest, abdomen, and pelvis. There is no

clear role for PET/CT in this setting.28

Surgery

5 It is clear that the only curative option in patients with gallbladder cancer is complete surgical

resection. It is essential for optimal patient care that patients with gallbladder cancer be recognized

before laparoscopic cholecystectomy is performed, because of the risk of bile spillage, with its potential

for subsequent carcinomatosis.29

Role of Staging Laparoscopy

Because a large percentage of patients with gallbladder cancer are found to have occult, unresectable

disease at the time of surgical exploration, several authors have investigated the use of initial staging

laparoscopy for this disease.30–33 Because gallbladder cancer has such a propensity to spread intraabdominally, this tumor is ideal for detection of intra-abdominal metastases with laparoscopy. This is

demonstrated by the fact that up to 50% of patients are found to have unresectable disease at the time

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of laparoscopy.34,35 Patients who are found to have unresectable disease at laparoscopy can begin other

forms of systemic therapy earlier and may undergo the procedure as an outpatient. Particularly because

patients with unresectable disease have a median survival of only 6 months, the impact on quality of

life, including decreased length of stay in the hospital, cannot be overemphasized.

Figure 63-2. Endoscopic retrograde cholangiopancreatogram obtained from a patient with gallbladder cancer. Mid–bile duct

obstruction (arrow) is caused by direct extension of tumor to the cystic and common hepatic duct.

Cholecystectomy With or Without Partial Hepatectomy

Gallbladder cancer, if not completely surgically removed, results in rapid local progression and death. In

a collected review of 5,836 patients with gallbladder cancer, the overall mean survival was between 2

and 5 months, whereas the 5-year survival was 4%.5 The 5-year survival of patients undergoing

resection with curative intent was 17%. Of the 2,115 patients with unresectable disease, only a single

survivor was found at 5 years. Although surgical resection represents the treatment of choice and the

only potentially curative therapy available, resection is possible in only 25% of patients at presentation

because of the advanced nature of the disease.5

Figure 63-3. T1-weighted magnetic resonance imaging scan of a patient with gallbladder cancer (small arrows) with extension into

the duodenum and the hepatic flexure of colon (large arrows).

There is little doubt that the results of treatment, as well as the scope of operation, are related to

depth of tumor penetration (Table 63-2). For tumors limited to the muscular layer of the gallbladder

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(T1), there is near-universal agreement that simple cholecystectomy is adequate.15,36–38 T1 tumors have

not yet invaded the subserosal layer, which contains lymphatics, and therefore lymphadenectomy is not

required. Attesting to the fact that early gallbladder carcinoma is completely curable, simple

cholecystectomy has resulted in 90% to 100% survival when early cancer is an incidental finding after

elective cholecystectomy.15,47

RESULTS

Table 63-2 Five-Year Survival After Resection for Gallbladder Cancer

RESULTS

Table 63-3 Results After Radical Resection for Gallbladder Cancer

Difficulty can arise at the time of surgery in evaluating polypoid lesions of the gallbladder as either

benign or early gallbladder cancer. Although it appears that frozen section diagnosis is fairly reliable in

distinguishing whether lesions are malignant or benign (95% accurate), the accuracy in correctly

assessing depth of invasion is only 70%.47 Thus, it may be difficult at the time of surgery to determine

the extent of resection. Because of this, pursuing a more aggressive resection if the depth of invasion is

in doubt is important for adequate tumor clearance.

The extent of surgical resection for T2 or greater tumors is controversial, with recommendations

ranging from simple cholecystectomy to radical excision, including hepatectomy. For advanced local

disease, some groups have advocated radical resections, including hepatectomy and pancreatectomy.

Whereas it is clear that major hepatic resection can be performed safely with a mortality less than 5%

(Table 63-3) it has not been universally accepted that more aggressive resections, such as combined

hepatectomy and pancreaticoduodenectomy, improve survival.14,15,36,37,40,48

To understand the rationale for extensive resections, it is also important to understand the pattern of

spread of gallbladder cancer. Direct extension to the adjacent liver parenchyma often occurs first,

followed by adjacent organ involvement, including duodenum, colon, and stomach (Fig. 63-2).

Lymphatic spread of gallbladder cancer is routine, often involving nodes in the porta hepatis,

peripancreatic region, celiac axis, and the aortocaval nodal basins. There is currently no consensus on

the extent of lymphadenectomy that is appropriate for gallbladder cancer. Extensive lymphadenectomy

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including para-aortic nodes is advocated in the East, but is not universally accepted. Recently, a

technique of intraoperative nodal staging was proposed that entails sampling the highest peripancreatic

lymph node for frozen section. This is the lymph node situated between the N1 and N2 nodal stations at

the junction of the bile duct and the superior border of the head of the pancreas (Fig. 63-4). Metastatic

disease to this node has been shown to be a poor prognostic factor.49

Figure 63-4. Illustration of the highest peripancreatic lymph node.

Because the gallbladder is not surrounded by serosa where it is attached to the liver in the gallbladder

fossa, even T2 tumors (full-thickness invasion of the muscular layer into the perimuscular connective

tissue, no extension beyond serosa or into liver) can invade the normal plane of dissection in the

gallbladder fossa during simple cholecystectomy. Therefore, T2 tumors cannot be completely removed

with cholecystectomy alone, and a radical cholecystectomy, with resection of a 1- to 2-cm rim of normal

liver around the gallbladder fossa, is the minimal resection that is required. Many authors, however,

have found that segmental resection of segments IVb and V of the liver, which abut the gallbladder

fossa, results in a more anatomically controlled dissection with less blood loss.50 An additional part of

the definitive surgical treatment is regional lymphadenectomy, because about half the patients with T2

tumors are found to have nodal spread after resection.14 Dissection of lymph nodes should include all

tissues from the bifurcation of the hepatic ducts to the distal CBD. Proponents of this approach advocate

liver resection on the basis that it is the only way to obtain an adequate margin on the hepatic side of

the gallbladder and resection of the regional nodes allows the best chance for complete tumor clearance.

For all of these reasons, simple cholecystectomy is inadequate for T2 or greater tumors. When larger

anatomic hepatic resections have been performed in patients with T2 tumors, it has increased the 5-year

survival from 25% to 40% after simple cholecystectomy to 70% to 100% after radical

resection.14,36–38,39,43,44,51,52

For T3 and T4 lesions, there is a high likelihood of intraperitoneal and hematogenous spread and

significant morbidity from the radical procedures that are often necessary for excision of local disease.

Recent series, however, support an aggressive approach to resection of these large tumors, particularly

if no indication of nodal involvement is found (Table 63-3). For T3 and resectable T4 tumors, a minimal

resection includes segments IVb and V, and in many cases an extended right hepatectomy (segments IV,

V, VI, VII, and VIII) may be necessary to obtain complete resection. With aggressive resection, longterm survival can be achieved even for patients with these more advanced tumors.14,15,36,37,40,53

Surgical exploration should be performed for all patients without medical contraindications. If a T1

tumor is suspected, a cholecystectomy and biopsy of regional nodes should be performed after thorough

examination of the abdominal cavity for any signs of tumor dissemination. The pathology and depth of

penetration should be confirmed by frozen section, and the procedure terminated if a T1 tumor with

negative margins is confirmed. For T2 lesions, either a radical cholecystectomy (wedge resection of the

hepatic bed) or a segment IVb and V resection with lymphadenectomy should be performed.14 For T3

lesions, a segment IVb and V resection or extended right hepatectomy is performed. Finally, for T4

lesions, a more radical excision of the liver, such as extended right hepatectomy, usually must be

performed for adequate tumor clearance.

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