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.

Epidemiology

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

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]

Pathology

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.

TABLE 1

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]

Cholangiocarcinoma

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]

TABLE 2

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]

Clinical Presentation

The symptoms related to gallbladder carcinoma and cholangiocarcinoma are relatively nonspecific, which in part accounts for the often delayed diagnosis. With a high index of suspicion and the advent of better imaging techniques, a preoperative diagnosis of gallbladder carcinoma may be reached in 75% to 88% of cases.[21]

The presentation of gallbladder or cholangiocarcinomas can be divided into five syndromes[22]:

(1) Acute cholecystitis: About 5% of patients operated upon for acute cholecystitis have occult gallbladder neoplasms. An incidence of 6% to 8% has been reported in elderly patients with acute cholecystitis, especially when associated with abnormal liver enzymes.[23] Therefore, it may be reasonable to consider offering patients with abnormal liver function tests an open cholecystectomy instead of a laparoscopic procedure.[24]

(2) Chronic cholecystitis: Recurrent cholecystitis in a patient over age 50 with known gallstone disease should raise suspicion for gallbladder cancer.[25]

(3) Biliary tract disease: Symptoms of biliary obstruction such as jaundice, right upper quadrant pain, nausea, vomiting, and in later stages, pruritus are often associated with unresectable disease. Mirizzi syndrome-obstructive jaundice due to compression of the common hepatic duct by an impacted stone in the gallbladder neck-has been associated with a high incidence of gallbladder cancer, and in such circumstances, intraoperative frozen section is recommended.[26]

(4) Nonspecific symptomatology: Anorexia, weight loss, and generalized weakness are common symptoms related to gallbladder cancer. Symptoms can also result from local complications such as fistula formation, invasion of an adjacent organ presenting with hemobilia, gastrointestinal bleeding, or intestinal obstruction. The presence of a palpable right upper quadrant mass indicates unresectability in most cases of gallbladder carcinoma.[27]

(5) Symptoms and signs related to metastatic disease Patients with gallbladder cancer can present with ascites, hepatomegaly, and paraneoplastic syndromes such as acanthosis nigricans. Most of these symptoms can be caused by gallstone disease alone.

Diagnostic Evaluation

TABLE 3

Common Diagnostic Procedures in the Diagnosis of Gallbladder Carcinoma

Imaging studies guide preoperative diagnosis, determine stage, and help assess resectability (Table 3). Multiple discontiguous liver metastasis, ascites, peritoneal metastasis, distant metastasis, extensive involvement of the hepatoduodenal ligament, encasement or occlusion of major vessels, biliary involvement not amenable to reconstruction, and poor performance status are indications of unresectable disease.[5] Direct involvement of duodenum, liver, or colon is not a contraindication to surgery.

Laparoscopy

Laparoscopic staging should be considered prior to laparotomy in potentially resectable disease because of high rates of occult metastatic disease. The overall accuracy of laparoscopy in detecting unresectable disease is 50% to 56%, which is more the result of detecting peritoneal metastasis than for locally advanced disease.[ 28,29] If the patient has radiologically unresectable disease, pathologic diagnosis can be obtained by needle biopsy to proceed with palliative therapy.

Ultrasonography

Ultrasonography is the most common radiologic study used to assess gallbladder disease. Findings suggestive of gallbladder cancer are discontinuous gallbladder mucosa, mural thickening, mural calcifications, a mass protruding into the lumen, a fixed mass in the gallbladder, loss of the interface between the gallbladder and the liver, or direct liver infiltration.[30] All gallbladder polyps larger than 1 cm, sessile polyps, and those with eroded mucosa are suspicious for carcinoma and should be resected.[31-33] Duplex and B-mode ultrasonography may be able to delineate biliary, vascular, or nodal involvement, but the sensitivity is only around 50%.[34,35]

Ultrasonography can evaluate potential cholangiocarcinomas by revealing dilatation of intrahepatic and/or extrahepatic ducts, which in the absence of gallstones and in the presence of any discrete narrowing is extremely suggestive of an obstructing malignancy.[36] The diagnostic accuracy of ultrasonography for cholangiocarcinoma is limited in the setting of primary sclerosing cholangitis or cirrhosis.

Endoscopic ultrasound may be useful in predicting the depth of tumor involvement, defining the lymph nodal involvement at the porta hepatic or peripancreatic region, and obtaining biliary cytology.[35,37] Endoscopic ultrasound-guided fine-needle aspiration is safe and effective in providing a definitive diagnosis of gallbladder and biliary tract carcinomas.[38,39]

Computed Tomography

Computed tomography (CT) scans are inferior to ultrasonography in the detection or evaluation of primary gallbladder tumors but are more useful in determining resectability by better assessing extent of disease.[40] Helical CT scans can predict resectability with 93.3% accuracy.[41] CT scanning is a poor modality for evaluation of contiguous spread of gallbladder cancer and detection of omental spread.[42,43] CT scans are sensitive in the detection of intrahepatic bile duct carcinomas[44] but limited in predicting resectability of cholangiocarcinoma, with accuracy ranging from 60% to 70%.[45]

Other Diagnostic Tools

Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are useful in obtaining biliary cytology for diagnosis. Biliary cytology may be positive in about 75% cases of gallbladder cancer, but the procedure involves the risk of biliary contamination, cholangitis, and sepsis. ERCP and PTC are often used as therapeutic measures to relieve biliary obstruction by placement of a stent. Noninvasive procedures such as magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) have generally replaced these procedures, as they better define resectability.[46]

MRI with MRCP is effective in preoperative evaluation of gallbladder carcinoma and cholangiocarcinoma.[ 46,47] The sensitivity of MRI and MRCP in studies has ranged from 67% to 100% for direct liver invasion and 56% to 92% for lymph node metastasis.[46,48]

Elevated carcinoembryonic antigen (CEA) and CA19-9 in the presence of biliary obstruction and nonspecific symptoms raises the suspicion of gallbladder cancer, but the sensitivity of CEA is only 50% and that of CA19-9 is approximately 80%.[49,50]

Surgical Management

Gallbladder Carcinoma

TABLE 4

Surgical Management of Gallbladder Carcinoma

The only potentially curative therapy for gallbladder cancer is complete surgical resection (Table 4). Historical data on the results of curative surgical resections have been disappointing until the last decade. A review of all cases of gallbladder cancer reported in the English literature up until 1978 (5,836 cases) reported a 5-year survival rate of less than 5%, with a median survival of 5 to 8 months.[51] For the 25% who were treated with curative-intent surgery, 5-year survival was only 16.5%. Similar results were seen in a French Surgical Association survey of 724 cases of gallbladder cancers, with a median survival of 3 months and survival rates of only 14% at 1 year and 5% at 5 years.[52]

In the past decade, however, better understanding of the patterns of tumor spread and progress in preoperative radiologic evaluation have led to better patient selection and an appreciation of the need for aggressive surgical resection for cure. Complete resection must include removal of the cancerous gallbladder, any adjacent organ invaded by tumor, and any potentially involved lymph nodes. Prognostic factors predicting successful resection include tumors limited to subserosal mucosa, hepatic infiltration of 5 mm or less, papillary or well-differentiated adenocarcinomas, absence of venous, lymphatic, or perineural invasion, and lymph node metastasis limited to the hepatoduodenal ligament.[53]

• Guidelines by Tumor Stage-T1 tumors are typically diagnosed incidentally after simple cholecystectomy for presumed gallstones. If a T1 tumor is discovered intraoperatively, the cystic lymph node should be excised and the portal lymph nodes carefully evaluated, although they are unlikely to be involved. If a T1 tumor is identified pathologically after conclusion of the operation, no further surgery is warranted. Simple cholecystectomy is usually curative for T1 tumors, with 5-year survival rates ranging from 85% to 100%.[54-57] Pathologic findings should be reviewed to make certain surgical margins are clear. If the cystic duct margin is positive, patients should undergo a common bile duct excision and biliary reconstruction.[3] In a case of laparoscopic cholecystectomy for unsuspected gallbladder carcinoma, frozen sections may be effective in predicting T2 or greater lesions for which conversion to radical cholecystectomy would be required.[58]

For patients undergoing exploration, a full abdominal exam should be performed looking for peritoneal metastasis, as this would preclude radical surgery.[59] Because of the tendency of gallbladder cancer to recur in laparoscopic port sites, these should be excised at the time of reexploration.[60,61]

Simple cholecystectomy is inadequate surgery for T2 lesions. The standard subserosal plane for surgical excision during routine cholecystectomy often violates a T2 tumor leading to positive margins.[57,62] Furthermore, lymph node metastases are found accompanying 33% of T2 tumors.[62] Appropriate surgical care for a T2 tumor is radical cholecystectomy, which involves removal of the gallbladder with at least 2 cm of the surrounding liver (segments IVB and V), and en bloc lymphadenectomy of the hepatoduodenal ligament lymph nodes, with or without bile duct excision.[51,57,63-66] Radical re-resection for a pathologic T2 lesion discovered after a simple cholecystectomy significantly improves survival.[54,67,68] In some studies, the survival benefit is limited to tumors associated with cancer cells within 5 mm of the excised margin at the initial cholecystectomy.[69,70]

Radical resection for T3 and T4 gallbladder disease-especially in the absence of nodal metastasis-has gathered support in recent years, with data confirming 5-year survival rates of 15% to 67% and 7% to 33% for T3 and T4 tumors, respectively.[65,69-74]

• Lymph Node Involvement-For patients with N1 disease, regional lymphadenectomy may cure metastasis to cystic, portal, and portocaval lymph nodes. Five-year survival rates ranging from 45% to 60% have been reported for patients with regional N1 disease after radical resection.[71,75] Radical lymphadenectomy for N2 disease, which involves removal of retropancreatic, periduodenal, periportal, superior mesenteric, aortocaval, or celiac lymph nodes, has been advocated by few investigators. Surgery includes a hepatopancreaticoduodenectomy in addition to radical cholecystectomy. However, this approach has been associated with high morbidity and mortality rates.[72] Therefore, radical resection should be reserved for patients with stage I to III disease-ie, tumor invasion up to T3, with nodal involvement confined to the hepatoduodenal ligament, posterosuperior pancreaticoduodenal region, and along the common hepatic artery.[76]

Cholangiocarcinoma

Complete excision of the tumor with bilioenteric anastomosis offers the only hope for long-term survival in cholangiocarcinoma. The rates of curative resection for intrahepatic, perihilar, and distal cholangiocarcinomas are approximately 60%, 56%, and 91%, respectively. Resection rates increase with more distal lesions.[11] Surgery for hilar cholangiocarcinomas requires excision of the supraduodenal bile duct, cholecystectomy, portal lymphadenectomy, and restoration of bilioenteric continuity. Management of more distal cancers includes pancreaticoduodenectomy.

TABLE 5

Criteria for Unresectability of Hilar Cholangiocarcinoma

Curative resection with histologically negative margins (R0) has been associated with a substantially improved 5-year survival of about 30%, as compared to only a 2-year median survival in the presence of histologically positive margins (R1). Performance of a partial hepatectomy, often but not necessarily with caudate lobectomy, seems necessary to achieve histologically negative margins for hilar cholangiocarcinomas. Recently, the postoperative morbidity and mortality associated with partial hepatectomy has fallen to less than 10%, making the operation feasible. Table 5 summarizes the criteria of unresectablity for a cholangiocarcinoma.[77,78]

Financial Disclosure:Dr. Kozuch receives grant support from Pfizer (irinotecan) and Sanofi-Synthelabo.

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