In Brief

Article Outline

• Copyright

Adenocarcinomas of the gallbladder and extrahepatic bile ducts are rare tumors with a traditionally poor overall prognosis. As a result, extensive clinical experience required to develop an understanding of the diagnosis, biologic behavior, and treatment of these tumors has been limited to a select number of highly specialized surgical centers. Their management is often complicated by the fact that many tumors do not manifest until they have become locally advanced or metastatasized. Developments in radiologic imaging technology; an increased understanding of portal, biliary, and hepatic anatomy; and the increasing safety of hepatobiliary surgery have led to an increasingly aggressive approach to the surgical management of these tumors and improvements in the long-term outcome. Although tumors of the gallbladder and extrahepatic biliary tree share many common embryologic, histologic, and anatomic elements, their etiology, biologic behavior, and management are unique and merit independent consideration.

Carcinomas of the gallbladder are relatively rare, affecting approximately 1 to 2 people per 100,000 in North America. The incidence of gallbladder cancer shows significant geographic variation, with high numbers of cases reported in Northern India, Pakistan, East Asia, Eastern Europe, and South America. Certain ethnic groups appear to have high rates of gallbladder cancer, including the Hispanic and Native American populations. Gallbladder cancers are more common among women especially in India and South America. Numerous risk factors for gallbladder cancer have also been identified including gallstones, porcelain gallbladder, gallbladder polyps, increased parity, obesity, Salmonella and Helicobacter infection, as well as the anomalous pancreaticobiliary duct junction (APBDJ) anatomic variant. These factors suggest a strong influence of genetic and environmental factors in the etiology of gallbladder cancer and have led to the proposal of two main pathways for the development of gallbladder cancer. The first pathway involves the formation of gallstones, cholecystitis, and infection resulting in chronic inflammation of the gallbladder, which in turn leads to malignant transformation. This pathway is influenced by obesity, gender, hormonal features, and unidentified genetic factors and leads to a higher proportion of females affected by this disease. The second pathway is associated with the APBDJ malformation and is commonly seen in East Asian populations. These two proposed pathways likely have different genetic pathways that may share common mutational targets such as K-ras, p53, and the epidermal growth factor receptor (EGFR) pathway as well as the loss of heterozygosity at several genetic loci including 3p, 8p, 9p, and 17p.

Pathologically, more than 90% of gallbladder cancers are adenocarcinomas. Gallbladder adenomas and dysplasia have been identified as premalignant lesions although the adenoma/dysplasia-carcinoma sequence has not been clearly defined and it is unclear what proportion of cancers develop from these lesions. The risk of malignancy in gallbladder adenomas is proportional to the size of the polyp, with approximately 90% of invasive cancers found in polyps greater than 1 cm in size. For this reason most centers advocate cholecystectomy for patients with gallbladder adenomas larger than 1 cm. Histologically, adenocarcinoma of the gallbladder can be classified as papillary, intestinal, mucinous, signet-cell, and clear cell. Gross pathologic subtypes include papillary, nodular, and infiltrative forms. There is significant correlation between histologic and gross pathologic subtypes, which in turn are associated with certain tumor biology characteristics including patterns of growth and local and metastatic spread.

Gallbladder cancer can be detected based on clinical presentation or incidentally following cholecystectomy for presumed benign disease. Cases of gallbladder cancer that are diagnosed based on clinical presentation or diagnostic imaging are often highly advanced at the time of detection. Symptoms can include abdominal pain, fullness/mass, weight loss, and jaundice; signs of ascites, hepatomegaly, and paraneoplastic syndromes portend incurable highly advanced or metastatic disease. The diagnostic evaluation of patients with potentially resectable lesions includes a combination of ultrasound, contrast enhanced computed tomography (CT), and magnetic resonance cholangiopancreatography (MRCP). Recent data suggest an emerging role for integrated positron emission tomography (PET)-CT in the evaluation of these lesions.

Many early gallbladder cancers manifest as incidental findings on the pathologic review of specimens from cholecystectomies performed for (presumed) benign disease, often in elderly patients. Although there is considerable debate about how to manage these cases, evidence suggests that incidental tumors confined to the lamina propria (Tis or T1a) can be treated with cholecystectomy alone and require no further management. Cancers that penetrate the muscularis propria (T2 or greater) require a subsequent radical en bloc resection and lymphadenectomy to improve local control and long-term survival. The management of tumors that invade but do not penetrate the muscularis (T1b) is controversial, but most centers would advocate radical re-resection and lymphadenectomy for these lesions based on the available literature.

The extent of resection to optimize the chances of cure in gallbladder cancer remains the subject of some debate. The critical components of resection include hepatectomy, bile duct resection, and lymphadenectomy; with each component tailored in each individual case. Hepatectomy has varied from a simple wedge resection of segments 4/5 for early fundal tumors to routine extended right hepatectomy. Lymphadenectomy has generally included clearance for the hepatoduodenal ligament but has been extended to retropancreatic and celiac nodes in some centers. Routine bile duct resection has been advocated based on a high degree of ductal and periductal spread in some tumor types; this also facilitates a more complete lymphadenectomy, with some centers including pancreaticoduodenectomy in some cases to improve the completeness of ductal clearance and lymphadenectomy. In all, a right trisectionectomy with resection of the extrahepatic bile duct and portal lymphadenectomy is considered the current standard of care for gallbladder cancer, although the extent of the operation can be modified based on the tumor characteristics or patient factors.

There has been considerable effort to improve the outcome for patients with gallbladder cancer through effective chemotherapy, but until recently efforts to develop effective regimens have been hampered by inadequate clinical volume and poor participation in multicentered trials. Recent reports have demonstrated promising results for gemcitabine/capcitabine-, oxaliplatin-, and cisplatin-based regimens. Radiotherapy has potential benefit, but the evidence supporting its routine use in the adjuvant, neoadjuvant, or palliative setting is still limited.

Cancers of the extrahepatic bile ducts, known also as Klatskin tumors or proximal cholangiocarcinoma, are similar to gallbladder cancer in that they are rare tumors with a poor overall prognosis. It is estimated that between 2500 and 4000 cases are diagnosed in the United States per year and as a result an extensive surgical experience with these tumors is limited to several high-volume hepatobiliary surgical centers. Fortunately, the increasing sensitivity resolution of diagnostic imaging techniques, increased appreciation of hepatobiliary anatomy, advances in surgical technique, and improvements in postoperative care have increased the safety of potentially curative surgery, enabled an increasingly aggressive surgical approach, and improved short- and long-term outcomes.

Although most patients who develop proximal cholangiocarcinoma lack a predisposing condition, several risk factors for bile duct cancer have been identified. These risk factors include primary sclerosing cholangitis, liver fluke infection, bile duct stones, and congenital cystic dilation of the biliary tree and all appear to induce preneoplastic and malignant changes in the biliary epithelium through chronic inflammation. This inflammation likely induces autonomous activation of the epidermal growth factor receptor (EGFR) and RAF/mitogen activated protein kinase (MAPK) pathways along with other inflammatory mediators such as cyclooxygenase, interleukin-6, and tumor necrosis factor alpha.

The majority of bile duct cancers are adenocarcinomas and are commonly referred to as cholangiocarcinomas. Adenosquamous and squamous cell cancers are also possible, particularly in choledochal cysts and cases of chronic choledochlithiasis. Histologically and macroscopically, cholangiocarcinomas can be classified as nodular, sclerosing, and papillary subtypes, with each type displaying a distinct pattern of tumor growth and spread. The papillary subtype grows as intraductal papillary projections and is associated with a better prognosis.

Tumors of the extrahepatic bile duct usually develop in patients older than 40 years and are detected at an asymptomatic stage as an incidental finding through the detection of an elevated serum liver profile or on radiologic investigations performed for other indications. Unfortunately, many tumors are diagnosed after the development of complete biliary obstruction with the appearance of jaundice resulting from tumor progression to involve the hepatic duct confluence. The diagnostic imaging assessment of these tumors uses multiple complimentary modalities including CT, ultrasound, and MRCP. In many cases, particularly in the sclerosing type, the tumor itself can be difficult to visualize and its extent must be inferred from the degree and location of biliary obstruction.

Many staging systems have been suggested to guide the surgical approach and predict the prognosis. The original classification system by Bismuth and Corlette is still widely used to describe the location and extent of the ductal involvement but does not describe the extraluminal extent of the tumor or predict prognosis. The current American Joint Committee on Cancer (AJCC) staging system describes the tumor extent and invasion of adjacent vessels and structures in a manner that likely predicts resectability and survival. Janagin and the investigative group at Memorial Sloan-Kettering have proposed their own staging system that classifies tumors based on the involvement of secondary biliary radicles, ipsilateral or contralateral portal vein, as well as hepatic lobar atrophy.

Curative, or R0, resection is the only potentially curative treatment for cholangiocarcinoma, but only a minority of patients are diagnosed with disease that is potentially resectable. Careful surgical planning is critical and includes the assessment of the extent of ductal involvement, the radial extent of the tumor, vascular involvement, and the presence of hepatic atrophy and hypertrophy. The increased safety of hepatobiliary surgery has facilitated an increasingly aggressive approach to these tumors that has resulted in increased resectability rates, higher R0 resection rates, and improved long-term outcome. Extended hepatic resection with caudate lobe resection, complete excision of the extrahepatic biliary tree, portal lymphadenectomy with selective portal vein resection, and pancreaticoduodenectomy is the accepted surgical approach that has been advocated by many Japanese surgical centers and slowly adopted in North America and Europe. Portal vein embolization and biliary drainage of the future remnant liver may increase the safety of extended hepatic resection. A few selected centers have recently published series of neoadjuvant chemotherapy and radiation followed by liver transplantation for cholangiocarcinoma, but this approach remains controversial and experimental.

Due to its similar pathologic characteristics, cancers of the gallbladder and bile ducts are often combined in clinical trials of chemotherapy or radiation. Therefore, the improved results obtained with gemcitabine/capcitabine-, oxaliplatin-, and cisplatin-based regimens can be applied to patients with bile duct cancer as well. Radiotherapy remains experimental and there are ongoing trials to assess its role. In addition, brachytherapy using treated biliary stents has been considered.