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Gallbladder carcinoma
Annals of Oncology 10 Suppl. 4: S129-S130,1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands.
Review. Gallbladder carcinoma Bernard Levin The University of Texas M.D.Anderson Cancer Center, Division ofCancer Prevention, 1515 Holcombe Boulevard, Box 203, Houston, TX 77030, U.S.A.
Summary Carcinoma of the gallbladder has an unusual geographic and demographic distribution being more common in Israel, Bolivia, Chile and in Southwestern native Americans in the United States. Chronic cholecystitis, choledochal cysts and significantly high body mass index are associated risk factors. Over 90% of gallbladder carcinomas are adenocarcinomas. Advanced local and regional disease usually is present at the time of diagnosis. P53 protein overexpression and p53 mutation may be related to increasing grade of cy tologic atypia and to invasi veness. K-ras gene mutation occurs in both dysplasia and carcinomas. Ultrasonography, CT, MRI are diagnostic measures that can
Epidemiology Adenocarcinoma of the gallbladder is the fifth most common gastrointestinal malignancy [1]. Autopsy and data from surgical series reveal an average incidence of gallbladder carcinoma ranging from 0.55% to 1.91% [2]. Gallbladder carcinoma is diagnosed most frequently in the sixth and seventh decades of life. There is a three-fold higher incidence in females than in males. In the United States, the incidence is highest in New Mexico where carcinoma of the gallbladder accounts for 8.5% of all cancers [3]. This observation is attributable to a very high prevalence among southwestern Native American1 women. Very high rates, 13.8 per 100,000 women and 7.5 per 100,000 men are reported from Israel [3]. High rates of gallbladder cancer also occur in Bolivia, Chile and northern Japan. Gallbladder cancer incidence rates are low in Singapore, India and Nigeria (Table 1). Table 1: Incidence of gallbladder cancer High
Low
New Mexico (Native Americans) Israel Mexico Bolivia Chile Northern Japan
India Nigeria Singapore
Causative factors (see Table 2) There is a significant association between
provide accurate staging information. Overall, the curative resection rates for gallbladder carcinoma range from 10% to 30%. During laparoscopic cholecystectomy, gallbladder cancer may be inadvertently discovered necessitating a more extensive resection. For those with unresectable disease, palliative surgical, endoscopic or radiologic bypass procedures can improve quality of life. Other approaches to the management of advanced tumors include combined radiation and chemotherapy and systemic chemotherapy. Key words: cholecystitis, gallbladder cancer, K-ras, p53
gallstones, chronic cholecystitis, and gallbladder carcinoma. Gallstones are present in 74% to 92% of patients with gallbladder carcinoma [4]. The risk of developing gallbladder cancer increases with increasing gallbladder size [5]. Cancer is more likely to occur with a single large gallstone than with multiple smaller stones. Approximately 1% of patients who undergo cholecystectomy for cholecystitis have an unsuspected gallbladder cancer. Table 2: Risk factor for gallbladder cancer • • • • • • •
Gallstones; chronic cholecystitis Gallbladder polyps - Peutz-Jeghers syndrome Choledochal cysts Anomalous pancreaticobiliary junction Industrial exposure to carcinogens "Porcelain" gallbladder ?High body mass index
Premalignant changes including epithelial hyperplasia, dysplasia and carcinoma have been identified in 13.5%; 8.3% and 3.5% respectively of patients undergoing cholecystectomy for cholelithiasis or cholecystitis [5]. Patients with choledochal cysts have an increased incidence of gallbladder cancer as well as malignant neoplasms throughout the biliary tract. The association of an anomalous junction between the common bile duct and the pancreatic duct with gallbladder cancer has also been described [3]. Other epidemiological studies have reported an association of gallbladder cancer with industrial exposure to azotoluenes and nitrosamines [1]. Patients with longstanding chronic cholecystitis can develop calcification of the gallbladder
130 wall, a condition known as "porcelain" gallbladder. An increased risk for gallbladder cancer has also been reported with an elevated body mass index; compared with those with a body mass index less than 24 Kg/m2, those with an index of 24-25 Kg/ m2, 26-28 Kg/ m2, and greater than 28 Kg/ m2, had odds ratios of 1.6 (CI, 0.4-7.6), 1.3 (CI, 0.3-5.06) and 2.6 (CI, 0.5-18.6), respectively (asymptotic test for trend, P=0.03) [6].
Pathology More than 80% of gallbladder cancers are adenocarcinomas. Papillary, tubular and nodular sub-types have been described. Well differentiated tumors have a better prognosis while poorly differentiated infiltrative tumors with associated gallstones are more likely to be associated with lymph node metastases and invasion into the liver [7]. Advanced, local and regional disease usually is present at the time of diagnosis. p53 protein overexpression and p53 gene mutation are related to increasing grade of atypia [8] and invasiveness [9]. It has been suggested that two main morphological pathways exist for development of gallbladder cancer, viz. de novo and an adenoma carcinoma sequence. Evidence has been presented that de novo carcinoma develops from a predominant p53 alteration with low K-ras mutation while carcinoma arising from preexisting adenoma develops through a p53-, K-ras- and APCgene-unrelated, as yet unknown, alteration [1].
Diagnosis The most common symptoms and signs are non-specific and include right upper quadrant abdominal pain and tenderness. Nausea, vomiting, anorexia, jaundice and weight loss also occur. Forty-five percent of patients are jaundiced at clinical presentation [1] and concomitant elevation of other liver enzymes is common. Imaging studies include ultrasonography, CT Scan and magnetic resonance cholangiography.
Resection Curative resection rates range from 10% - 30% [11]. The majority of patients are not candidates for curative resection because of extensive local-regional involvement, noncontiguous liver and/or distant metastases. For Tla, NoMo lesions, simple cholecystectomy may be adequate. In patients with Tib or AJCC TNM Stage II and m gallbladder carcinomas, an extended cholecystectomy resulted in a fiveyear survival rate ranging from 7.5% to 37%, whereas those treated with simple cholecystectomy had a 0% 5-year survival rate [1]. Laparoscopic cholecystectomy may inadvertently be the precipitating event in the discovery of a gallbladder cancer. If not appropriately handled, inadvertent spillage of tumor cells into the peritoneal cavity is possible. If unsuspected
preoperatively, the diagnosis at the time of laparoscopy should prompt an open definitive surgical resection.
Palliation In patients with unresectable tumors, palliation of jaundice by surgical bypass or endoscopically or radiologically placed drainage tubes is often necessary. Systemic or regional chemotherapy has been attempted with only modest success. Radiation therapy either alone or in combination with systemic chemotherapy has been used with occasional long term survivorship [1].
References 1.
Curley SA, Levin B, Rich TA. Liver & Bile Duct. In Clinical Oncology. New York, New York: Churchill Livingstone, Inc, Abeloff MD, Armitage JO, LichterAS.NiederhuberJE(eds), 1995: 1305-18. 2. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg GynecolObstet 1978: 147:929. 3. Pitt HA, Dooley WC, Yeo CI et al. Malignancies of the biliary tract Curr ProblSurg 1995:32:1 4. Nagormey DM, McPherson GAD. Carcinoma of the gallbladder and extrahepatic bile ducts. Semin Oncol 1998: 15:106 5. Black WC. The morphogenesis of gallbladder carcinoma. In Progress in Surgical Pathology. Masson, New York: Fenoglio CM, Wolff M (eds), 1980: 207. 6. Strom BL, Soloway RD, Dios-Dalenz JL et al. Risk factors for gallbladder cancer. Cancer 1995: 76:1747-56. 7. Sumiyoshi K, Nagai E, Chijiiwa K et al. Pathology of carcinoma of the gallbladder. WorldJSurg 1991: 15:315 8. Itoi T, Watanabe H, Yoshida M et al. Correlation of p53 protein expression with gene mutation in gallbladder carcinomas. Pathology International 1997: 47:525-30. 9. Roa I, Villaseca M, Araya JC et al. DNA ploidy pattern and tumor suppressor gene p53 expression in gallbladder carcinoma. Cancer Epidemiology, Biomarkers and Prevention 1997: 6:547-50. 10. Itoi T, Watanabe H, Ajioka Y et al. APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gallbladder suggest two genetic pathways in gallbladder carcinogenesis. Pathology International 1996: 46:333-40.
Correspondence to: Bernard Levin, M.D. The University of Texas M. D. Anderson Cancer Center Division of Cancer Prevention 1515 Holcombe Boulevard, Box 203 Houston, TX 77030, U.S.A.
Review. Gallbladder carcinoma Bernard Levin The University of Texas M.D.Anderson Cancer Center, Division ofCancer Prevention, 1515 Holcombe Boulevard, Box 203, Houston, TX 77030, U.S.A.
Summary Carcinoma of the gallbladder has an unusual geographic and demographic distribution being more common in Israel, Bolivia, Chile and in Southwestern native Americans in the United States. Chronic cholecystitis, choledochal cysts and significantly high body mass index are associated risk factors. Over 90% of gallbladder carcinomas are adenocarcinomas. Advanced local and regional disease usually is present at the time of diagnosis. P53 protein overexpression and p53 mutation may be related to increasing grade of cy tologic atypia and to invasi veness. K-ras gene mutation occurs in both dysplasia and carcinomas. Ultrasonography, CT, MRI are diagnostic measures that can
Epidemiology Adenocarcinoma of the gallbladder is the fifth most common gastrointestinal malignancy [1]. Autopsy and data from surgical series reveal an average incidence of gallbladder carcinoma ranging from 0.55% to 1.91% [2]. Gallbladder carcinoma is diagnosed most frequently in the sixth and seventh decades of life. There is a three-fold higher incidence in females than in males. In the United States, the incidence is highest in New Mexico where carcinoma of the gallbladder accounts for 8.5% of all cancers [3]. This observation is attributable to a very high prevalence among southwestern Native American1 women. Very high rates, 13.8 per 100,000 women and 7.5 per 100,000 men are reported from Israel [3]. High rates of gallbladder cancer also occur in Bolivia, Chile and northern Japan. Gallbladder cancer incidence rates are low in Singapore, India and Nigeria (Table 1). Table 1: Incidence of gallbladder cancer High
Low
New Mexico (Native Americans) Israel Mexico Bolivia Chile Northern Japan
India Nigeria Singapore
Causative factors (see Table 2) There is a significant association between
provide accurate staging information. Overall, the curative resection rates for gallbladder carcinoma range from 10% to 30%. During laparoscopic cholecystectomy, gallbladder cancer may be inadvertently discovered necessitating a more extensive resection. For those with unresectable disease, palliative surgical, endoscopic or radiologic bypass procedures can improve quality of life. Other approaches to the management of advanced tumors include combined radiation and chemotherapy and systemic chemotherapy. Key words: cholecystitis, gallbladder cancer, K-ras, p53
gallstones, chronic cholecystitis, and gallbladder carcinoma. Gallstones are present in 74% to 92% of patients with gallbladder carcinoma [4]. The risk of developing gallbladder cancer increases with increasing gallbladder size [5]. Cancer is more likely to occur with a single large gallstone than with multiple smaller stones. Approximately 1% of patients who undergo cholecystectomy for cholecystitis have an unsuspected gallbladder cancer. Table 2: Risk factor for gallbladder cancer • • • • • • •
Gallstones; chronic cholecystitis Gallbladder polyps - Peutz-Jeghers syndrome Choledochal cysts Anomalous pancreaticobiliary junction Industrial exposure to carcinogens "Porcelain" gallbladder ?High body mass index
Premalignant changes including epithelial hyperplasia, dysplasia and carcinoma have been identified in 13.5%; 8.3% and 3.5% respectively of patients undergoing cholecystectomy for cholelithiasis or cholecystitis [5]. Patients with choledochal cysts have an increased incidence of gallbladder cancer as well as malignant neoplasms throughout the biliary tract. The association of an anomalous junction between the common bile duct and the pancreatic duct with gallbladder cancer has also been described [3]. Other epidemiological studies have reported an association of gallbladder cancer with industrial exposure to azotoluenes and nitrosamines [1]. Patients with longstanding chronic cholecystitis can develop calcification of the gallbladder
130 wall, a condition known as "porcelain" gallbladder. An increased risk for gallbladder cancer has also been reported with an elevated body mass index; compared with those with a body mass index less than 24 Kg/m2, those with an index of 24-25 Kg/ m2, 26-28 Kg/ m2, and greater than 28 Kg/ m2, had odds ratios of 1.6 (CI, 0.4-7.6), 1.3 (CI, 0.3-5.06) and 2.6 (CI, 0.5-18.6), respectively (asymptotic test for trend, P=0.03) [6].
Pathology More than 80% of gallbladder cancers are adenocarcinomas. Papillary, tubular and nodular sub-types have been described. Well differentiated tumors have a better prognosis while poorly differentiated infiltrative tumors with associated gallstones are more likely to be associated with lymph node metastases and invasion into the liver [7]. Advanced, local and regional disease usually is present at the time of diagnosis. p53 protein overexpression and p53 gene mutation are related to increasing grade of atypia [8] and invasiveness [9]. It has been suggested that two main morphological pathways exist for development of gallbladder cancer, viz. de novo and an adenoma carcinoma sequence. Evidence has been presented that de novo carcinoma develops from a predominant p53 alteration with low K-ras mutation while carcinoma arising from preexisting adenoma develops through a p53-, K-ras- and APCgene-unrelated, as yet unknown, alteration [1].
Diagnosis The most common symptoms and signs are non-specific and include right upper quadrant abdominal pain and tenderness. Nausea, vomiting, anorexia, jaundice and weight loss also occur. Forty-five percent of patients are jaundiced at clinical presentation [1] and concomitant elevation of other liver enzymes is common. Imaging studies include ultrasonography, CT Scan and magnetic resonance cholangiography.
Resection Curative resection rates range from 10% - 30% [11]. The majority of patients are not candidates for curative resection because of extensive local-regional involvement, noncontiguous liver and/or distant metastases. For Tla, NoMo lesions, simple cholecystectomy may be adequate. In patients with Tib or AJCC TNM Stage II and m gallbladder carcinomas, an extended cholecystectomy resulted in a fiveyear survival rate ranging from 7.5% to 37%, whereas those treated with simple cholecystectomy had a 0% 5-year survival rate [1]. Laparoscopic cholecystectomy may inadvertently be the precipitating event in the discovery of a gallbladder cancer. If not appropriately handled, inadvertent spillage of tumor cells into the peritoneal cavity is possible. If unsuspected
preoperatively, the diagnosis at the time of laparoscopy should prompt an open definitive surgical resection.
Palliation In patients with unresectable tumors, palliation of jaundice by surgical bypass or endoscopically or radiologically placed drainage tubes is often necessary. Systemic or regional chemotherapy has been attempted with only modest success. Radiation therapy either alone or in combination with systemic chemotherapy has been used with occasional long term survivorship [1].
References 1.
Curley SA, Levin B, Rich TA. Liver & Bile Duct. In Clinical Oncology. New York, New York: Churchill Livingstone, Inc, Abeloff MD, Armitage JO, LichterAS.NiederhuberJE(eds), 1995: 1305-18. 2. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg GynecolObstet 1978: 147:929. 3. Pitt HA, Dooley WC, Yeo CI et al. Malignancies of the biliary tract Curr ProblSurg 1995:32:1 4. Nagormey DM, McPherson GAD. Carcinoma of the gallbladder and extrahepatic bile ducts. Semin Oncol 1998: 15:106 5. Black WC. The morphogenesis of gallbladder carcinoma. In Progress in Surgical Pathology. Masson, New York: Fenoglio CM, Wolff M (eds), 1980: 207. 6. Strom BL, Soloway RD, Dios-Dalenz JL et al. Risk factors for gallbladder cancer. Cancer 1995: 76:1747-56. 7. Sumiyoshi K, Nagai E, Chijiiwa K et al. Pathology of carcinoma of the gallbladder. WorldJSurg 1991: 15:315 8. Itoi T, Watanabe H, Yoshida M et al. Correlation of p53 protein expression with gene mutation in gallbladder carcinomas. Pathology International 1997: 47:525-30. 9. Roa I, Villaseca M, Araya JC et al. DNA ploidy pattern and tumor suppressor gene p53 expression in gallbladder carcinoma. Cancer Epidemiology, Biomarkers and Prevention 1997: 6:547-50. 10. Itoi T, Watanabe H, Ajioka Y et al. APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gallbladder suggest two genetic pathways in gallbladder carcinogenesis. Pathology International 1996: 46:333-40.
Correspondence to: Bernard Levin, M.D. The University of Texas M. D. Anderson Cancer Center Division of Cancer Prevention 1515 Holcombe Boulevard, Box 203 Houston, TX 77030, U.S.A.