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

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.