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Gallbladder and Biliary Tract Carcinoma: A Comprehensive Update, Part 1

Gallbladder and Biliary Tract Carcinoma: A Comprehensive Update, Part 1

ABSTRACT: Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. These cancers are often diagnosed in an advanced stage due to their nonspecific symptomatology and until recently have been associated with a dismal prognosis. Recent advances in imaging and surgical techniques along with emerging options in palliative chemotherapy have improved the outlook in these cancers. While complete surgical resection remains the only hope of cure in both these cancers, palliative biliary decompression and chemotherapy result in substantial improvement in quality of life. Part 1 of this review provides a relevant and comprehensive update of molecular pathology, imaging modalities, and surgical care. In part 2, which will appear next month, we will review palliative care and systemic therapy in gallbladder and biliary tract carcinomas, as well as the use of liver transplantation in the treatment of cholangiocarcinomas. These strategies are of relevance to internists as well as oncologists caring for these patients.

Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. Gallbladder cancer is the more common biliary tumor in this country, accounting for about 5,000 cases per year.[1] Until recently, gallbladder cancer was associated with a dismal prognosis. A better understanding of the disease, its patterns of spread, and its potential for cure with radical surgery as well as advances in various diagnostic tools have led to improved survival in recent years. Moreover, improvements in palliative care including biliary decompression techniques and chemotherapy have expanded treatment options for these diseases. Cholangiocarcinoma, cancer of the bile ducts, accounts for about 2,500 cases annually in the United States.[2,3]

Cholangiocarcinoma may be further classified as intrahepatic or extrahepatic (hilar and distal bile duct carcinomas). The hilar tumors usually require partial liver resection for cure, whereas distal tumors may require pancreatectomy. As with gallbladder tumors, advances in diagnostic imaging techniques permit earlier diagnosis of these cancers and careful selection of potentially resectable disease. The search for appropriate neoadjuvant or adjuvant treatments to improve survival outcomes and decrease recurrences is ongoing.

Part 1 of this two-part review summarizes advances in preoperative imaging, staging, and curative surgery. In part 2, which will appear in next month's issue, we will explore chemotherapy, radiation therapy, and palliative care, which are improving the outlook for patients diagnosed with these cancers.


Gallbladder Cancer

Carcinoma of the gallbladder is a rare malignancy generally associated with a late presentation and a poor prognosis. Nonmetastatic lesions carry a 5-year survival rate of 32%, whereas more advanced stages have a 1-year survival rate of only 10%.[4] Affecting 1 to 2 people per 100,000, gallbladder cancer is the fifth most common cancer of the gastrointestinal tract in the United States,[3] where between 2,000 and 5,000 cases of gallbladder cancer are diagnosed each year.[1,3]

Incidence varies throughout the world, with the most diagnoses and highest mortality occuring in northern India, northeastern Europe, and in native populations in North and South America. Mortality rates in these areas can reach 5 to 10 times that in the United States.[4] Western Native Americans and Hispanic Americans are at an increased risk compared to the general US population, while African Americans have been placed at equivalent or slightly decreased risk compared to the Caucasian population.[4,5] Increased risk also is noted in women in Japan and Israel.[6] The ratio of affected women to men is variable according to region, ranging between 1.5:1 and 6:1.[4,5,7] Risk increases with age, with the maximum incidence occurring in the 7th decade.[3]

Risk Factors—Gallbladder carcinoma has been linked to several risk factors. Gallstones and chronic cholecystitis commonly are associated with the development of gallbladder cancer, although neither is known to play a strictly causative role.[6] Between 50% and 100% of patients diagnosed with gallbladder cancer have concurrent stones.[7] The incidence of neoplasm in patients with gallstones and no other risk factors or symptoms, however, is very low (< 1%).[1,4] The presence of larger gallstones may be related to increased risk; patients with gallstones larger than 3 cm are at 10 times the risk of patients with stones smaller than 1 cm.[4,5] The incidence of cancer in calcified (porcelain) gallbladder has been estimated at 12.5% to 61%.[6] Chronic inflammation of the gallbladder, polyps, bacterial infections, typhoid carrier status, ulcerative colitis, and congenital anomalous pancreaticobiliary duct junction also increase risk.[5,6]

Although the imbalance of women vs men suggests a role for hormonal changes, disease pathogenesis studies examining this role are inconclusive.[5,6] Women with a history of three or more pregnancies are at increased risk. Late onset of menarche and increased age at first childbirth (> 20 vs < 20 years) has been observed to decrease risk.[6,8]

The geographic distribution of disease elicits continued investigation into dietary and genetic risk factors. High energy and high total carbohydrate intake have been linked to gallbladder cancer. The odds ratio associated with high energy intake is 2.0, while the ratio associated with total carbohydrate consumption is 11.3. A significant reduction in risk has been associated with increased vitamin B6 and vitamin E consumption. Vitamin C, fat, and dietary fiber intake have also been shown to provide modest protection. High body mass index is associated with a 2.1- fold increase in risk in women, but risk in men has not been observed to relate to body mass index.[8]

Occupational exposures in the rubber, automobile, wood-finishing, oil, paper, chemical, textile, shoe, fiber and metal-fabricating industries lead to increased risk.[4,6] Likewise, both tobacco chewing and smoking are associated with increased risk.[6] The consumption of carcinogenic impurities in mustard oil may contribute to elevated incidence in India.[5]


Cholangiocarcinoma-epithelial cancer of the cholangiocytes lining the biliary ducts-like gallbladder cancer, generally presents late and allows few options for curative intervention. Incidence estimates range from 0.8 to 2 per 100,000, with an estimated 2,500 to 4,000 new cases diagnosed each year in the United States.[2,3,7] Several recent studies indicate that the number of diagnoses of cholangiocarcinoma is increasing in the United States, United Kingdom, and Australia.[2] Some of this increase may be attributable to new methods of diagnosis for obstructive jaundice that identify extrahepatic malignancies that previously would have been misdiagnosed.[9] Incidence peaks in the 8th decade of life[9] and is slightly higher in men than in women.[10]

Risk Factors—Risk factors for cholangiocarcinoma are well understood, although most patients lack identifiable risks.[2] Patients with primary sclerosing cholangitis carry an elevated risk for cholangiocarcinoma of 1.5% per year from onset of disease and a lifetime risk of about 10%.[1,3] They usually present with multifocal and unresectable carcinomas.[ 3] Congenital choledochal cysts increase the risk of cancer, most likely due to associated inflammation and bacterial infection. While early removal of cysts lowers the likelihood of malignancy, 15% to 20% of patients with unexcised cysts or cysts treated by bypass will develop cancer.[3]

Chronic ulcerative colitis, liver infection, exposure to carcinogens (including thorium dioxide, asbestos, radon, dioxin, nitrosamines, and cigarette smoke), and chronic intrahepatic lithiasis are associated with increased risk of cholangiocarcinoma.[2,7] Approximately 2% of patients with hepatitis C develop cholangiocarcinoma,[7] and biliary parasites such as Opisthorchis viverrini and Clonorchis senensis contribute to increased risk, especially in Southeast Asia, where incidence can reach 87 per 100,000.[3]

Patients can present with cholangiocarcinoma in the intrahepatic, extrahepatic, or hilar regions of the biliary tract and generally do not survive for more than 6 months after diagnosis. The frequency of intrahepatic tumors ranges between 10% and 33%, whereas the frequency of extrahepatic and hilar cancers is 60% to 90%.[2,9] Less than 10% of patients have diffuse or multifocal tumors.[9] From 40% to 60% are perihilar and proximal to the cystic duct and usually require partial hepatic resection.[11] From 20% to 30% are distal to the cystic duct and are best treated with pancreaticoduodenectomy.[11]


Gallbladder Carcinoma

Most gallbladder cancers (99%) are adenocarcinomas.[12] Infrequently, tumors of the gallbladder can be of mesenchymal origin-leiomyosarcoma, rhabdomyosarcoma, or, more rarely, carcinosarcoma, small-cell carcinoma, carcinoid tumor, lymphoma, or melanoma. Gallbladder tumors can also be classified by their gross configuration as infiltrative (causing thickening and induration of the gallbladder), nodular, and papillary, which has the most favorable prognosis because of its minimal invasive quality.[13] Infiltrative tumors often present like a chronically inflamed gallbladder, and the tumors frequently are diagnosed only after cholecystectomy.

Gallbladder Cancer Staging System

Because of the proximity of the gallbladder to segments IVb and V of the liver, direct invasion by tumor occurs often. Gallbladder cancer metastases are common, with the incidence of lymphatic and hematogenous invasion reported in one study as 94% and 65%, respectively.[14] Cancer typically spreads around the bile duct, to the cystic and pericholedochal nodes. Later spread goes to portacaval and celiac nodes, then to retropancreatic, aortocaval, and superior mesenteric artery lymph nodes.[3,5] Direct invasion of the adjacent structures such as duodenum, colon, anterior abdominal wall, and common hepatic ducts is extremely common. More distant metastases to the lung and brain have been observed in 32% and 5% of patients, respectively.[15]

While knowledge of the molecular pathology of gallbladder cancer is limited, researchers have investigated the role of ras, TP53 (alias p53), and p16/CDKN2 abnormalities in gallbladder cancer pathogenesis.[4] Small studies report codon 12 K-ras mutations in 0% to 59% of patients and CDKN2 abnormalities in approximately half of all patients. Molecular pathogenesis is still unclear, although evidence seems to point toward an early and important role for p53 in the development of malignancy. Table 1 shows the commonly used TNM systems for staging of gallbladder cancer.[16,17]


Similar to gallbladder tumors, 90% of cholangiocarcinomas are adenocarcinomas and can be divided into sclerosing, nodular, and papillary subtypes.[ 18] Papillary tumors have been associated with improved outcomes in some retrospective analyses.[3]

Extrahepatic Bile Duct Staging System

Although the etiology of this neoplasm is unknown, considerable evidence points toward chronic inflammation as a source of malignant alterations. Proinflammatory cytokines contribute to the overexpression of nitric oxide synthase, which produces chemicals promoting mutagenesis and encouraging cell growth. Bile acids are believed to transactivate epidermal growth factor receptor and induce cyclooxygenase (COX)-2 expression, which in turn inhibits apoptosis and encourages cellular and vascular growth. Allelic loss of p53 and bcl-2 has been observed in 30% to 40% of tumors, while activation of the oncogenes K-ras (50%-75%), c-myc (95%), c-neu, c-erb-B2(0%- 73%), and c-met, as well as receptor tyrosine kinases, COX-2, and human aspartyl (asparaginyl) beta-hydroxylase also have been observed in limited series.[19] Disruptions of the p14/MDM/p53 signaling pathway and the retinoblastoma/p16/cyclin-dependent kinase 4 cell regulatory pathway have been found in both cholangiocarcinoma and primary sclerosing cholangitis, suggesting a common etiology or a causative role for the inflammatory condition.[19]

Cholangiocarcinoma metastasizes readily to the liver, pancreas, hepatic portal vein, hepatic artery, and lymphatic systems. The incidence of spread to the liver or peritoneum has been reported to approach 50%, while spread to regional lymph nodes is observed in 75% to 80% of cases.[20] Table 2 shows the TNM system used to stage cholangiocarcinoma.[16]


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