The Patient with Postprandial Right Upper Quadrant Abdominal Pain

Key Supporting Information

Enhanced imaging technology associated with increased utilization has increased the recognition of biliary tract tumors. Approximately 5% of patients will have a gallbladder polyp when evaluated with ultrasonography for abdominal pain.1 Gall bladder carcinoma is the most common cancer of the biliary tree.1 There are multiple risk factors for this type of cancer including: female sex, gallstones, obesity, age >50 years, chronic infection with Salmonella typhi, porcelain gallbladder, and polyps greater than 1 cm in size.2 Approximately 90% of patients with gall bladder cancer have concomitant gallstones.2

In the United States, the incidence of gallbladder cancer is 1.2 cases/100,000, while the frequency is much higher in Native and Mexican Americans, with the greatest incidence in the indigenous peoples of the Andes Mountains, northeastern Europeans, and Israelis.2 In addition, patients with an anomalous pancreatic duct that drains into the lower common bile duct instead of the ampulla, are also at increased risk for gallbladder carcinoma. Peak incidence is in the seventh decade with a female-to-male ratio of approximately 3:1.2 The vast majority of gallbladder cancers are adenocarcinomas, with the remainder being squamous cell or other cancers (sarcoma, adenosquamous carcinoma, oat cell carcinoma, carcinoid, lymphoma, melanoma, and metastatic tumors).3 It spreads locally to the lymph nodes, peritoneal cavity, and the liver.

Although relatively uncommon when listed among all cancers, it is often fatal, often being diagnosed at an advanced stage. Well differentiated papillary adenocarcinoma, which represents about 5% of gallbladder cancers, carries a more favorable prognosis.4

It is possible to cure gallbladder cancer when tumors are treated surgically at an early stage. Because the size of a gallbladder polyp is the strongest predictor of malignant transformation, it is important to identify those that carry a high risk of malignancy. Prophylactic cholecystectomy should be considered with polyps greater than 1 cm (10 mm) in size, porcelain gallbladder, or gallstones greater than 3 cm.5

There are various kinds of gallbladder polyps, including: adenomatous, inflammatory, cholesterol polyps, and adenomyomatosis.6 Adenomatous polyps are benign neoplasms possessing malignant potential. These adenomas project into the gallbladder lumen, growing as pedunculated, branching tumors.7 Tubular adenomas develop as flat, sessile neoplasms that can undergo carcinomatous transformation.8 Inflammatory polyps can originate from chronic inflammation, protruding by a narrow vascularized stalk into the gallbladder lumen.9

Cholesterol polyps, which originate from a defect in cholesterol metabolism, account for approximately half of all polypoid lesions of the gallbladder.10 Histologically, these yellow spots on the mucosal surface of the gallbladder are epithelial-covered macrophages loaded with triglycerides and esterified sterols in the lamina propria of the gallbladder.10 These polyps usually occur as multiple lesions, usually less than 10 mm in size.10 Adenomyomatosis is characterized on ultrasound by a thickened gallbladder wall containing intramural diverticula.11 Microscopically, extensions of the Rokitansky-Aschoff sinuses penetrate through the muscular wall of the gallbladder.11

Most patients present with signs and symptoms consistent with cholecystitis, while others are found incidentally on ultrasound or CT examination. Almost half of gallbladder cancer cases are diagnosed incidentally in cholecystectomy specimens, with approximately 35% of patients having distant metastases at the time of diagnosis.12

The overall survival rate for adenocarcinoma of the gall bladder depends on the stage at presentation. In patients with early gallbladder cancer, cholecystectomy offers a possible cure when the cancer is confined to the mucosa (Stage I or T1/T2).13 When hepatectomy is used routinely for T1b or deeper lesions, many studies report 5-year survival rates of 100%.14 The 5-year survival rates following extended cholecystectomy for T2 lesions ranges from 38% to 77%. Tumor location may affect survival for T2 lesions.14 Extensive surgical resection is necessary for Stage III and IV tumors and results in 5-year survival of about 25%.14 Patients with unresectable disease have a median survival of 2 to 4 months and a 1-year survival rate of less than 5%.15

For patients with advanced disease, adjuvant and palliative chemotherapy have been utilized, although the benefits of adjuvant treatment remains unproven, and standard adjuvant treatment protocols are currently lacking. Phase 2 studies have shown that the use of single-agent chemotherapy (with capecitabine, gemcitabine, or 5-fluorouracil) in the palliative setting can have some benefit.16 Combination chemotherapy also has been shown to be beneficial and is usually based on gemcitabine, capecitabine, or 5-fluorouracil used in combination with cis-platinum or oxaliplatinum.17 Fluoropyrimidine-based chemoradiotherapy also has been utilized for palliative and adjuvant treatments.18

Cholangiocarcinomas are present in less than 0.2% of all cancers.19 They can be located within the liver or extrahepatically in the distal or perihilar ducts, with the perihilar cancers being the most common.19 Risk factors include hepatolithiasis, parasitic infection, toxin exposure, primary sclerosing cholangitis, choledochal cysts, and congenital dilatation or fibrosis of the biliary ducts. Genetic oncogenes, such as p53 and K-Ras, have been identified.20 Greater than 90% of these tumors are adenocarcinomas. The highest yearly incidence rates for this cancer are in Israel (7.3/100,000) and Japan (5.5/100,000).20 In most Western countries, the yearly incidence ranges from 2 to 6/100,000 with Native Americans having an incidence of 6.5/100,000. Prevalence rates are highest in the 6th and 7th decades of life.20

The most common clinical presentation is jaundice, abdominal pain and clay-colored stools with cholestasis and markedly increased alkaline phosphatase. Weight loss and pruritis can also be seen. The tumor marked CA 19-9 is elevated in up to 80% of cases.21 Courvoisier sign (palpable gallbladder) can be elicited if the carcinoma is distal to the cystic duct takeoff.

Abdominal CT, magnetic resonance cholangiopancreatography (MRCP), angiography, or cholangiography can be used to stage the disease and determine whether surgical resectability is a possible option. Surgery is not indicated in patients with occlusion or encasement of the portal vein or hepatic artery and peritoneal, liver, or lung metastases.22 Adjuvant chemotherapy and/or radiation have also been utilized as well as stenting, brachytherapy, radiofrequency ablation, and photodynamic therapy.23 Pain can be relieved with regional injection of a sclerosing agent or alcohol, particularly with retroperitoneal tumor growth.

If the tumor is deemed unresectable, stents can be placed with the aid of percutaneous transhepatic cholangiography or endoscopic retrograde cholangiopancreatography. Stenting may relieve biliary obstruction and pruritus, and improve quality of life.

Photodynamic therapy, which can be effective in improving biliary drainage, first involves the administration of a photosensitizer, followed by light illumination activation at an appropriate wavelength.24

Adjuvant and preoperative radiation therapy with and without concomitant chemotherapy has been used to decrease tumor size to make them resectable.

Primary chemotherapy, including gemcitabine and cisplatin, has also been utilized for inoperable biliary tract carcinoma. 5-fluorouracil has similar low partial response rates to gemcitabine.25 However, chemotherapy agents used without radiotherapy or surgery do not appear to provide any meaningful survival benefit.

Although fluoropyrimidines and doxorubicin have been reported to have higher initial partial response rates, the duration of benefit from weeks to months has been observed in only 10% to 35% of trials.26

Liver transplantation can be considered for some patients with proximal tumors who are not resection candidates. This may have a survival benefit over palliative treatments, especially for patients with early-stage tumors in the initial stages, with 1 study demonstrating a 5-year survival rate greater than 80% in certain patients.27