With an incidence of 6500 cases annually in the United States, gallbladder cancer is the fifth most common gastrointestinal tract malignancy in this country.1 Incidence increases with age and is two to six times higher in women than in men. Worldwide, the highest incidence rates (up to 7.5 per 100,000 in men and 23 per 100,000 in women) occur among populations in the Western part of South America (eg, Chile and Peru), in North American Indians, in Mexican Americans, and in northern India.2 The best characterized risk factor for the development of gallbladder cancer is chronic inflammation associated with gallstones (Table 51-1). Although only 0.5–3% of patients with cholelithiasis will develop gallbladder cancer, gallstones are present in 70–90% of patients diagnosed with gallbladder cancer.2–4 Further, the geographic pattern of gallbladder cancer incidence correlates with that of cholelithiasis.
Table 51-1: Risk Factors for Developing Gallbladder Cancer ||Download (.pdf)
Table 51-1: Risk Factors for Developing Gallbladder Cancer
|Adenomatous polyps of the gallbladder|
|Chronic Salmonella typhi infection|
|Carcinogens (eg, radon)|
|Abnormal pancreaticobiliary duct junction (APBDJ)|
Other factors implicated to increase the risk of developing gallbladder cancer include porcelain gallbladder (the incidence of gallbladder cancer is reported to range from 12.5 to 60% in patients with this condition),2–4 adenomatous polyps of the gallbladder (in contrast, cholesterol and inflammatory polyps and adenomyomas are not believed to be the risk factors), chronic infection with Salmonella typhi, carcinogen exposure (eg, increased risk has been reported for miners exposed to radon), and abnormal pancreaticobiliary duct junction (APBDJ). In this latter condition, a long common channel, formed by an abnormally proximal junction between the pancreatic and common bile ducts (CBDs), and elevated sphincter of Oddi pressures create a predisposition to reflux pancreatic exocrine secretions into the bile ducts. APBDJ is most prevalent in Asian countries and appears to increase the risk of development of biliary cancers, especially gallbladder cancer.5 Gallbladder cancers arising in patients with APBDJ tends to occur at a younger age, to have a lesser degree of female predominance, and to be less often associated with cholelithiasis than those arising in patients without APBDJ.
Pathogenesis and Pathology
Chronic inflammation of the gallbladder mucosa related to gallstones is hypothesized to be the major factor leading to malignant transformation in most cases of gallbladder cancer. The progression from dysplasia, to carcinoma in situ (CIS), then to invasive cancer has been described for gallbladder cancer. The molecular changes associated with this progression are under investigation: K-ras mutations appear to be relatively uncommon, whereas p53 mutations are prevalent and tend to arise early during this progression.2
Gallbladder cancers arising in patients with APBDJ may be associated with a distinct pathogenetic mechanism. These cancers are associated with a high prevalence of K-ras mutations and a late onset of p53 mutations.2 In addition, there is a high prevalence of premalignant epithelial hyperplasia with a papillary or villous histology in the gallbladder mucosa of patients with APBDJ.
Eighty percent of primary gallbladder cancers are adenocarcinomas. Other histological types include small cell cancer, squamous cell carcinoma, lymphoma, and sarcoma. Gallbladder cancers are also classified according to morphology as infiltrative, nodular, papillary, or a combination of these types. Papillary cancers tend to grow within the gallbladder lumen and are less likely to invade the liver or to metastasize to lymph nodes; it is associated with the best prognosis. Infiltrative or nodular cancers have a more diffuse pattern of growth that is difficult to recognize on imaging studies. These lesions are more likely to have invaded the liver and to have metastasized to lymph nodes by the time of diagnosis.
Several staging systems for gallbladder cancer have been described. The Nevin staging system, originally put forth in 1976, is of historical interest; the tumor, node, metastasis (TNM) system is used today (Table 51-2). The seventh edition of the American Joint Committee on Cancer (AJCC) staging system, published in 2010, contains important modifications to the staging of gallbladder cancer contained in the sixth edition.6 N stage now includes N1 (metastasis to cystic duct, CBD, hepatic artery, and/or portal vein lymph nodes) and N2 (metastasis to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes) designations. Stage classifications have been revised to better reflect patient outcomes. For example, locally unresectable T4 cancers are now classified as stage IV, whereas T4N0 cancers were classified as stage III in the sixth edition. M0 cancers associated with lymph node metastasis are now classified as stage IIIB (with N1 disease) or stage IVB (with N2 disease), whereas these cancers were classified as stage IIB or III (depending on T stage) in the sixth edition.
Table 51-2: TNM Staging of Gallbladder Cancer: American Joint Committee on Cancer, 7th Edition ||Download (.pdf)
Table 51-2: TNM Staging of Gallbladder Cancer: American Joint Committee on Cancer, 7th Edition
|Stage IVB||Any T||N2||M0|
|Any T||Any N||M1|
Clinical Presentation and Diagnosis
In the absence of advanced disease, patients with gallbladder cancer are asymptomatic or have symptoms, such as abdominal pain, anorexia, nausea, and vomiting, that may be indistinguishable from those of cholelithiasis or cholecystitis. With advanced disease, patients can present with weight loss, obstructive jaundice (due to tumor invasion into the biliary tree or to liver metastases), and duodenal obstruction. Signs associated with advanced disease include palpable abdominal masses, hepatomegaly, and ascites.
Laboratory tests may suggest obstructive jaundice if this condition is present; otherwise, they are not helpful in the diagnosis of gallbladder cancer. Tumor markers carcinoembryonic antigen (CEA) or CA 19-9 may be elevated; however, they lack sufficient sensitivity or specificity to be useful in clinical decision making for individual patients.
Patients with suspected gallstone- or gallbladder-related conditions typically undergo transabdominal ultrasonography (US). Findings suggestive of gallbladder cancer on ultrasonography include mural thickening or calcification, a gallbladder mass greater than 1 cm in diameter, and loss of the normal gallbladder wall–liver interface (Fig. 51-1). Relative to transabdominal ultrasonography, endoscopic ultrasonography (EUS) offers greater accuracy in assessing depth of gallbladder wall penetration by masses and regional lymph node enlargement. Selective application of EUS in patients with a gallbladder mass can help in the determination of whether the mass is non-neoplastic (eg, cholesterol pseudopolyp) or neoplastic. In addition, EUS-guided biopsy is an effective technique in cases in which a tissue diagnosis is required.
Ultrasound of gallbladder cancer. The images demonstrate asymmetric wall thickening of the body and neck of the gallbladder. (Used with permission from Dr. Steven E. Seltzer, Department of Radiology, Brigham & Women's Hospital; www.brighamrad.harvard.edu)
Computed tomography (CT) scanning should be performed on patients suspected of having gallbladder cancer. Findings of gallbladder cancer include a mass protruding into the gallbladder lumen or completely replacing the gallbladder and focal or diffuse thickening of the gallbladder wall (Fig. 51-2). CT scanning also offers information on the presence or absence of distant metastases, regional lymph node involvement, and local invasion into the liver and porta hepatis.
CT scan of gallbladder cancer. The image shows a 3.5 × 4 cm lesion arising from the gallbladder fundus and extending into segment 5 of the liver.
Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) can offer additional information on local invasion, particularly into the porta hepatis. These tests are used selectively, if CT findings are equivocal. Similarly, endoscopic or percutaneous cholangiography is not routinely indicated; they are used primarily for palliation or preoperative management of obstructive jaundice.
Surgical resection is the only known curative form of therapy for gallbladder cancer. For patients in whom surgical exploration is contraindicated because of medical comorbidities or evidence of unresectable disease on imaging studies (eg, metastatic disease), a percutaneous or endoscopic needle biopsy can be obtained to confirm the diagnosis. For patients in whom surgery is planned, a preoperative biopsy is contraindicated, as gallbladder cancer has a propensity for dissemination along needle tracts.
Recommendations for extent of surgical resection according to disease stage are given below. Specific technical issues are discussed subsequently.
For Tis (carcinoma in situ) and T1a (cancer that invades the lamina propria but does not extend into the muscularis) lesions, the available retrospective data suggest that simple cholecystectomy is sufficient therapy in most cases. These lesions are most frequently detected on pathological examination of gallbladders removed for presumed benign disease. Patients diagnosed with gallbladder cancer in this manner should undergo formal imaging-based staging, and the cholecystectomy specimen should be carefully examined to ensure that all margins are negative for cancer. Patients with imaging studies that reveal no evidence of residual or metastatic gallbladder cancer and are found to have a cystic duct margin that is positive for cancer should undergo re-exploration with common duct excision, regional lymphadenectomy, and hepaticojejunostomy. In contrast, patients with negative margins and negative imaging studies who undergo no additional treatment for their gallbladder cancer have excellent outcomes that are unlikely to be improved by radical surgery.7
The management of T1b (cancer that invades the muscularis but does not extend into the perimuscular connective tissues) lesions has been controversial. In published series, the 5-year survival rate for patients with T1b gallbladder cancer having undergone radical resection averages 87.5%, whereas it averages only 61.3% in patients having undergone simple cholecystectomy alone.8 Further, a recently published decision analysis suggests that radical surgery (described later for stage II cancers) is associated with improved survival compared to that associated with simple cholecystectomy alone in most patients with T1b gallbladder cancer.8 Therefore we treat patients with T1b gallbladder cancer in the same way we treat patients with T2 gallbladder cancer.
Patients found to have a T2 (cancer invasion into the perimuscular connective tissues of the gallbladder) lesion in their cholecystectomy specimen following surgery for presumed benign disease should undergo staging (as described earlier), and in the absence of contraindications, radical resection. Simple cholecystectomy is usually performed using a subserosal dissection plane, and, hence, may leave positive margins in the gallbladder fossa. Indeed, re-exploration reveals residual tumor in 40–76 % of these cases.9–12 In addition, the probability of regional lymph node metastasis in patients with T2 gallbladder cancer has been reported to range from 28 to 63%.9–12 These findings provide rationale for performing re-exploration with liver resection and regional lymphadenectomy of the hepatoduodenal ligament. There is convincing, albeit retrospective, evidence that such radical surgery is associated with improved survival for patients with T2 gallbladder cancer.9–12 Given the propensity of gallbladder cancer to seed wound sites, re-excision of all surgical wounds, including laparoscopic port sites, during re-exploration has traditionally been recommended. However, re-excising port sites can be difficult (the trajectory through which ports had traversed the abdominal wall during the initial operation may be impossible to determine at the time of definitive surgery), and the value of this practice is unproven.
Patients suspected of having a T2 gallbladder cancer preoperatively (prior to cholecystectomy) should undergo staging, and in the absence of contraindications, exploration with en bloc resection of the gallbladder and adjacent liver to a depth of at least 2 cm, in addition to regional lymphadenectomy of the hepatoduodenal ligament. Although a nonanatomic liver resection encompassing the gallbladder fossa can be applied at the time of re-exploration or en bloc with the gallbladder during the initial procedure, anatomical resection of liver segments 4b and 5 may be associated with less intraoperative bleeding.
A role for aggressive surgical resection for some stage III gallbladder cancers has been receiving increasing recognition. This stage includes T3 lesions (locally advanced cancers that perforate the gallbladder serosa or directly invade the liver and/or one adjacent organ) and T1–3 lesions associated with regional lymph node metastasis.
Surgery for patients with T3 lesions requires careful planning and must be tailored to individual patients. For some patients with liver invasion, hepatic resections encompassing segments 4b and 5 may be sufficient. However, because the gallbladder fossa bridges both right and left hepatic lobes, trisegmentectomy is often required. Adjacent involved structures, such as the hepatic flexure of the colon, should be resected en bloc. Long-term survival rates ranging from 15 to 63% have been reported from some centers to be associated with these extended procedures for T3 lesions.9–12
Stage IVA (invasion of the main portal vein, common hepatic artery, multiple extrahepatic organs) and stage IVB (N2 and/or distant metastasis) disease meet criteria for unresectability. Anecdotal reports of super-radical procedures involving resection of the main portal vein and/or common hepatic artery exist, but these procedures are associated with substantial morbidity and mortality rates and are unlikely to confer any survival benefits.
There is no evidence to support the application of debulking cholecystectomy to prevent subsequent episodes of cholecystitis; we do not recommend it.
For patients suspected of having resectable gallbladder cancer, we begin surgical exploration with laparoscopy. In the absence of disseminated disease, we proceed with open laparotomy. Because of the risk for gallbladder perforation and tumor spillage, we recommend against laparoscopic cholecystectomy in patients suspected of having gallbladder cancer. We also recommend early conversion to open laparotomy in patients undergoing laparoscopic cholecystectomy for presumed benign disease in whom the suspicion of gallbladder cancer arises intraoperatively.
We use a right subcostal incision, as it easily can be extended to a chevron incision if necessary. We then conduct a thorough examination for metastases, especially in the liver and on the peritoneal surfaces. For patients in whom the suspicion of gallbladder cancer is low at this point a simple cholecystectomy is done, and the gallbladder is examined using frozen-section analysis. Confirmation of T1b, T2, or T3 disease should prompt radical resection, as described later. If the diagnosis based on frozen-section analysis is ambiguous (ie, the presence of gallbladder cancer cannot be confirmed), radical surgery should be deferred. For patients in whom the suspicion of gallbladder cancer is high because of the presence of a firm mass, we obtain a small biopsy of the lesion. If the diagnosis of gallbladder cancer is confirmed on frozen-section analysis, the gallbladder is resected en bloc with the adjacent liver, as described later. Although determining depth of cancer invasion can be difficult on frozen sections, these grossly apparent cancers are likely to be T2 or more advanced lesions.
If radical resection is indicated, we then perform a Kocher maneuver to mobilize the duodenum and the head of the pancreas. Enlarged retropancreatic, celiac, superior mesenteric, or para-aortic lymph nodes are sampled and subjected to frozen-section analysis. If these lymph nodes are positive for metastases, N2 disease is present, and radical resection is aborted.
In the absence of N2 disease, we then perform regional lymphadenectomy. We skeletonize CBD and common hepatic duct, hepatic artery, and portal vein from the superior border of the duodenum to the liver hilum. During this dissection, lymph node–bearing fibrofatty tissues are swept toward the gallbladder and removed as a specimen. Tumor invasion of the portal vasculature is assessed during this dissection. We do not perform major vascular resection for advanced gallbladder cancer at our institution.
In contrast, we do perform common duct resection if the gallbladder cancer has invaded this structure. Common duct resection may also facilitate resection of bulky nodal disease in the hepatoduodenal ligament. The CBD is clamped and transected at the superior border of the duodenum, and its stump is oversewn with a nonabsorbable monofilament suture. Similarly, the common hepatic duct is transected near its bifurcation. We take care to minimize spillage of bile that may contain cancer cells.
We then perform en bloc resection of the gallbladder and the adjacent liver (or the liver resection alone if the patient has already undergone cholecystectomy). If the CBD has not been transected, the cystic duct is divided near its junction with the CBD. Similarly, the cystic artery is ligated and divided near its origin. For T2 cancers, either a nonanatomic wedge resection of the liver that encompasses the gallbladder fossa to a depth of 2 cm or anatomical resection of liver segments 4b and 5 is acceptable (Fig. 51-3). The capsule of the liver is scored with electrocautery to mark the resection plane. Overlapping chromic liver sutures are then placed around the periphery of the resection plane for hemostasis and retraction. The liver parenchyma is then transected using one of the standard methods (we usually use a combination of electrocautery and argon-beam coagulation). Care should be taken near the base of the liver resection margins to avoid injuring the right hepatic artery as it traverses inferiorly in the gallbladder fossa.
Radical resection of gallbladder cancer. This illustration depicts the operative field after radical cholecystectomy has been performed. The hatched line denotes the regions included in the lymphadenectomy.
If the common duct has been resected, a 60-cm Roux-en-Y limb of jejunum is used to create a hepaticojejunostomy. The anastomosis is constructed using a single layer of 5-0 absorbable sutures.
Adjuvant chemoradiotherapy is commonly administered after resection of gallbladder cancers. External beam or intraoperative radiation therapy alone or in combination with 5-flourouracil (5-FU) is associated with diminished rates of local recurrence. The impact of these regimens on survival is unclear; no data derived from prospective randomized clinical trials on the efficacy of these regimens exist.
The goals of palliative therapy are relief of pain, manifestation of biliary obstruction (eg, pruritis and cholangitis) and bowel obstruction. Given the limited expected survival duration of patients diagnosed with unresectable gallbladder cancer (weeks to months), endoscopic or percutaneous stenting, rather than surgical bypass, is generally recommended for relief of symptomatic biliary obstruction (Figs.51-4 and 51-5). Biliary stents are discussed in greater detail later in the section on palliation of bile duct cancers.
CT scan of advanced gallbladder cancer. The image demonstrates an advanced gallbladder cancer with extensive liver invasion. A stent has been placed for palliation of obstructive jaundice.
Palliation of gallbladder cancer. This radiograph depicts a Wallstent that has been placed for palliation of obstructive jaundice in a patient with advanced gallbladder cancer.
Palliative radiation therapy, regional intra-arterial chemotherapy, systemic chemotherapy, and chemoradiotherapy all have been applied in patients with advanced gallbladder cancer. Results of the ABC-02 trial were recently published.13 Data from this multicenter phase III trial of patients with locally advanced or metastatic biliary tract cancer (of whom ~36% had gallbladder cancer) demonstrated that the combination of gemcitabine plus cisplatin is associated with improved overall and progression-free survival than gemcitabine alone. As such, this gemcitabine-cisplatin combination represents the current standard treatment option for patients with advanced biliary tract cancers, including gallbladder cancer.14
Data derived from the National Cancer Database support the nihilistic view traditionally associated with gallbladder cancer.15 In these population-based data, 5-year survival rates for patients with T1N0, T2N0, and T3N0 (or node-positive) disease are 39, 15, and 5%, respectively.
However, contemporary surgical series suggest that substantially improved outcomes can be achieved by the application of surgical resection of gallbladder cancers.16 In these reports, 5-year survival rates following resection of T1 lesions ranges from 85 to 100%. With radical resection of T2, T3, and T4 lesions, reported 5-year postoperative survival rates range from 80 to 90%, 15 to 63%, and 2 to 25%, respectively. Radical resection of node-positive disease has been reported to be associated with 5-year survival in as high as 60% of patients, although some reported series contained no patients who survived 2 or more years among those with lymph node metastasis.9–12
Reported morbidity and mortality rates associated with resection of gallbladder cancers range from 5 to 54% and from 0 to 21%, respectively. In general the highest morbidity and mortality rates are associated with series describing more extensive resections.
The best reported outcomes among patients with unresectable biliary tract cancers are those from the ABC-02 trial.13 The median overall survival among patients treated with the combination of gemcitabine and cisplatin was 11.7 months, whereas it was 8.1 months in those treated with gemcitabine alone.13