Gallbladder cancer was first described in 1777.1 More than 200 years later, late diagnosis and absence of effective treatment for many patients remain typical features of this disease. The prognosis is poor—only about a 32 percent five-year survival rate for lesions confined to the gallbladder mucosa and a 10 percent one year survival rate for more advanced stages. The highest frequency of the disease is found among females over the age of 65. There is a marked regional and ethnic variation in the incidence of gallbladder cancer. The highest mortality rates have been reported among Chilean Mapuche Indians and Hispanics, among Bolivians, North American Indians, and Mexican Americans. Incidence rates are much lower in Europe and India.
Due to its non specific clinical presentation, it is seldom diagnosed preoperatively except in advanced cases. Survival depends on the ability to achieve a curative resection depending upon the stage of the disease. The overall surgical resection rates range from 10% to 30% only thereby indicating a poor prognosis. The etiology of carcinoma gall bladder is poorly understood. Chronic cholecystitis and gallstones, choledochal cysts, female gender, age and exposure to carcinogens and some neoplastic initiators, such as unknown endo- and exobiotic mutagens, or as neoplastic promoters, including chronic inflammation and infection. Among the latter factors, a link has been specifically proposed between chronic bacterial infection of the gallbladder with Salmonella typhi. a definite cause – effect relationship has yet to be established for any of these factors
EPIDEMIOLOGY
In autopsy studies throughout the world, gallbladder cancer represents 80 to 95 percent of cancers of the biliary tree The rates for gallbladder cancer are higher among women than men in all populations included in the analysis. The rates are highest in women from La Paz, Bolivia (15.5 per 100,000). Intermediate rates (from 3.7 to 9.1 per 100,000) are reported in Trujillo, Peru; Quito, Ecuador; Cali, Colombia; Porto Alegre, Brazil; Asuncion, Paraguay; and Montevideo, Uruguay. In North America, low rates predominate, with the exception of high rates reported among Indians in New Mexico (11.3 per 100,000) and intermediate rates among female immigrants from Latin America. In Europe, the highest incidence is found in the countries of Eastern Europe: Poland (Krakow), the Czech Republic, and Slovakia. The incidence increases progressively with age, both in males and females, in all populations. The highest mortality rate of gallbladder cancer in the world, 35 per 100,000 inhabitants, is found in Southern Chile (the region of the Araucania), which is inhabited by Chilean Hispanics and Mapuche Indians
PATHOGENESIS
Although it has been established that dysplasia and carcinoma in situ precede most gallbladder carcinomas, relatively little is known about the natural history of these precursor lesions. Most dysplasias and carcinomas in situ are diagnosed after cholecystectomy when the entire lesion is removed.
If multiple sections of gallbladders removed for cholelithiasis are examined, dysplasia and carcinoma in situ are detected in 13.5 percent and 3.5 percent of the cases, respectively. Over 90 percent of gallbladder carcinomas are adenocarcinomas. Gallstones are found in almost all cases of gallbladder cancer (78 percent to 85 percent). Most carcinomas (60%) originate in the fundus of the gallbladder, 30% in the body, and 10% in the neck. The prevalence of gallbladder cancer associated with diffuse calcification of the gallbladder (so-called porcelain gallbladder) is 12 to 21 percent. Most gallbladder cancers are well-to-moderately differentiated adenocarcinomas.
Some of these are papillary lesions that grow predominantly into the lumen of the
gallbladder. The main prognostic factor for gallbladder carcinoma is the clinical or pathologic stage There is a correlation between level of tumor invasion in the gallbladder wall and the presence of lymph node metastases. The gallbladder’s very thin wall and the discontinuous muscular layer are believed to facilitate tumor invasion and contribute to the advanced local and regional disease usually present at the time of diagnosis.
RISK FACTORS
Among other risk factors, a number of genetic, dietary factors, endo- and exobiotics, and chronic gallbladder infections, have been associated with the development of gallbladder cancer. However, the primary risk factor of gallbladder cancer as reported in all studies is gallstone disease.
CHOLELITHIASIS
Cholelithiasis is frequently associated with carcinoma gallbladder in up to 40%-100% patients and is the most common associated factor independent of age or sex. The risk of carcinoma gallbladder in patients with gallstones may be increased 4 to 7 times, and patients with gallstones >3cm in diameter have a much higher risk. Gallstones were found in 45% of our cases of carcinoma gallbladder. Carcinoma gallbladder is known to develop in patients with gallbladder preserving therapies for cholelithasis. However, the mode of carcinogenesis is not clear. It has been shown that chronic trauma and inflammation can induce epithelial dysplasia, carcinoma in situ and invasive cancer but a cause and effect relation has not been unequivocally proved.
CHRONIC CHOLECYSTITIS
Approximately 50% patients of carcinoma of the gallbladder have a history suggestive of chronic cholecystitis. It has been reported that carcinoma gallbladder may develop in 10% of patients with xanthogranulomatous cholecystitis.
PORCELAIN GALLBLADDER
There is a 20% risk of developing carcinoma gallbladder in patients with calcified or porcelain gallbladder making this an absolute indication for cholecystectomy.
GALLBLADDER POLYPS
Even though a definitive evidence similar to the adenoma carcinoma sequence in colonic cancer is lacking in carcinoma gallbladder, recent studies suggest that polyps greater than 10mm in diameter have a strong malignant potential. In one study by Kozuka et al, all the adenomas showing malignant change were larger than 12mm in diameter. If diagnosed in asymptomatic patients, cholecystectomy is recommended even in the absence of. However, for polyps <>CONGENITAL ANOMALIES
Recent studies have suggested that anomalous pancreaticobiliary duct junction (APBDJ) is a risk factor for carcinoma gallbladder. Gallbladder carcinoma occurred in 25% of the 65 patients with an anomalous union of the 2 duct systems as compared with 1.9% among 635 consecutive patients with a normal duct union. Anomalous duct union is seen in approximately 17% patients with carcinoma gall bladder as compared with less than 3% among patients with other hepatobiliary disorders. It is thought that this anomalous junction allows the free reflux of pancreatic juice into the gallbladder, the stasis of which damages the gallbladder mucosa and causes precancerous changes.
BILE AND BACTERIA
Primary bile acids are degraded to the secondary bile acids by anaerobic organisms in the large bowel, some of which are thought to be implicated in colonic carcinogenesis. Fox et al identified the presence of Helicobacter species in bile and gallbladder tissue from patients with cholelithiasis and cholecystitis but its relevance in carcinoma of the gallbladder is not yet established. A study from one centre has clearly shown significantly higher secondary bile acid in carcinoma of the gallbladder with positive culture. Among the different microbial agents salmonella typhi has been implicated frequently.
DIAGNOSIS
Early carcinoma gallbladder has no specific clinical presentation and preoperative diagnosis is rarely possible. Most of these patients are asymptomatic while a few present with clinical features suggestive of benign disease such as right upper abdominal pain interspersed with occasional attack of nausea and vomiting. In one study al, 48.2% of patients of carcinoma gallbladder had a preoperative diagnosis of symptomatic cholelithiasis. About 1% of patients operated for acute cholecystitis are found to have carcinoma gallbladder. Jaundice, presence of a lump and features of malignant cachexia such as anorexia and weight loss are a feature of extensive disease as is the presence of repeated attacks of vomiting which suggests gastric outlet obstruction due to tumour infiltration. The presence of a hard nodule in the liver and ascites indicates disseminated disease. In 15-20% of patients, carcinoma gallbladder is discovered either intraoperatively or postoperatively on histology, which in only 20% of the patients is the disease confined to gallbladder at diagnosis. The majority of the patients thus have locoregionally advanced or metastatic disease on first presentation.
TREATMENT
The treatment depends primarily upon the stage of the disease at presentation. The only potentially curative therapy is surgical resection. Unfortunately the overall resection rates at presentation range from 10%-30% only. Broadly management guidelines can be divided into three clinical groups.
1. Incidentally discovered carcinoma gallbladder during laparotomy or after cholecystectomy for benign disease.
2. Carcinoma gallbladder suspected or confirmed preoperatively on diagnostic workup.
3. Advanced carcinoma gallbladder diagnosed clinically or by preoperative investigations.
Carcinoma gallbladder is incidentally discovered during cholecystectomy for benign diseases in 12-36% of patients. If carcinoma gallbladder is discovered intraoperatively the surgeon has to decide whether curative surgery is possible after determining the extent of disease. If the disease is so extensive as to preclude curative resection then a biopsy along with the appropriate palliative procedure may be carried out. Sometimes the probability of carcinoma gallbladder becomes evident only after the gallbladder is opened up after removal hence it is important to examine the opened gallbladder carefully before closing the abdomen. More commonly, however it is only after histopathological examination of the diagnosis is made. Further treatment of such cases remain controversial. While most authors feel that simple cholecystectomy is adequate if the tumour has not invaded beyond the muscle layer reporting 5 year survival rates of nearly 100% The surgical management of carcinoma gallbladder diagnosed preoperatively depends upon the extent of the disease determined either by investigations or at laparotomy. Patients with disease confined to the gallbladder are treated by extended or radical cholecystectomy, but for disease extending beyond the gallbladder extended or radical cholecystectomy offers little, if any, survival advantage. Donohue et al reported a 5 year survival of 29% after extended cholcecystectomy in patients with transmural (T3, T4) tumour invasion and lymph node involvement as compared to no survivors after simple cholecystectomy in this group of patients. Matsumoto et al, Nakamura et al, Ogura et al and Ouchi et al advocate more extensive surgery such as excision of bile ducts, more extensive liver resections and even pancreaticoduodenectomy to further increase survival rates. Although some long term survivors have been reported, the morbidity and mortality of these procedures is high (48-54% and 15- 18% respectively) especially in patients with obstructive jaundice. Nakamura et al reported 54% 1 year survival, 23% 2 year survival and 15% 5 year survival rate for patients with TNM stage IV carcinoma gallbladder. The criteria for respectability can vary but presence of multiple peritoneal or liver metastases, distant metastases, extensive involvement of hepatoduodenal ligament, encasement or occlusion of major vessels and poor performance status are contraindications for surgical resection. Direct involvement of colon, duodenum or liver however, are not absolute contraindications for resectional surgery. In patients not fit for tumour resection, some form of palliative procedure such as a surgical bilioenteric bypass or endoscopic/percutaneous stenting in patients with obstructive jaundice may be done. Since the level of tumour obstruction is usually at the common hepatic duct or above, the round ligament approach to the segment III duct along with a biliary enteric anastamoses provides good palliation. In the presence of tumour invasion of the umbilical fissure of the liver, segment III bypass is not possible and recourse has to be taken for an alternative approach such as the Longmire procedure. Advances in endoscopic and radiologically guided percutaneous stenting have made operative bypass procedures in patients with unresectable cancer largely redundant. For patients with distal common bile duct obstruction an endoscopically placed stent provides good palliation whereas the percutaneous approach does the same for more proximal obstructions. These patients rarely live long enough to require stent replacement.
PROGNOSIS AND SURVIVAL
The stage at presentation is the most important prognostic determinant. Presently, the overall survival of carcinoma of the gallbladder is extremely discouraging. Hension et al, have shown 2 year survival is 45% for stage I, 15% for stage II, 4% for stage III and 2% for stage IV. Medical survival is 19, 7, 4 and 2 months for stage I, II, III and IV disease respectively. If the serosal layer is invaded the 5 year survival decreases to 91% if resection margins are negative on reexploration and to 43% with positive resection margins.
J Cancer Res Clin Oncol 1993;119(3):165-171; Gastroenterology 1998;115:937-946; Cancer 1992;70: 410-414; Am J Surg Pathol 1984; 8:323-333;Br J Surg 1990, 77: 363;Langenbecks Arch Surg 2000, 382: 501-508;Br J Surg 1994, 81: 1655-1657;Cancer 1995, 76: 1747-1756;World J Surg 2003, 27: 266-271
Due to its non specific clinical presentation, it is seldom diagnosed preoperatively except in advanced cases. Survival depends on the ability to achieve a curative resection depending upon the stage of the disease. The overall surgical resection rates range from 10% to 30% only thereby indicating a poor prognosis. The etiology of carcinoma gall bladder is poorly understood. Chronic cholecystitis and gallstones, choledochal cysts, female gender, age and exposure to carcinogens and some neoplastic initiators, such as unknown endo- and exobiotic mutagens, or as neoplastic promoters, including chronic inflammation and infection. Among the latter factors, a link has been specifically proposed between chronic bacterial infection of the gallbladder with Salmonella typhi. a definite cause – effect relationship has yet to be established for any of these factors
EPIDEMIOLOGY
In autopsy studies throughout the world, gallbladder cancer represents 80 to 95 percent of cancers of the biliary tree The rates for gallbladder cancer are higher among women than men in all populations included in the analysis. The rates are highest in women from La Paz, Bolivia (15.5 per 100,000). Intermediate rates (from 3.7 to 9.1 per 100,000) are reported in Trujillo, Peru; Quito, Ecuador; Cali, Colombia; Porto Alegre, Brazil; Asuncion, Paraguay; and Montevideo, Uruguay. In North America, low rates predominate, with the exception of high rates reported among Indians in New Mexico (11.3 per 100,000) and intermediate rates among female immigrants from Latin America. In Europe, the highest incidence is found in the countries of Eastern Europe: Poland (Krakow), the Czech Republic, and Slovakia. The incidence increases progressively with age, both in males and females, in all populations. The highest mortality rate of gallbladder cancer in the world, 35 per 100,000 inhabitants, is found in Southern Chile (the region of the Araucania), which is inhabited by Chilean Hispanics and Mapuche Indians
PATHOGENESISAlthough it has been established that dysplasia and carcinoma in situ precede most gallbladder carcinomas, relatively little is known about the natural history of these precursor lesions. Most dysplasias and carcinomas in situ are diagnosed after cholecystectomy when the entire lesion is removed.
If multiple sections of gallbladders removed for cholelithiasis are examined, dysplasia and carcinoma in situ are detected in 13.5 percent and 3.5 percent of the cases, respectively. Over 90 percent of gallbladder carcinomas are adenocarcinomas. Gallstones are found in almost all cases of gallbladder cancer (78 percent to 85 percent). Most carcinomas (60%) originate in the fundus of the gallbladder, 30% in the body, and 10% in the neck. The prevalence of gallbladder cancer associated with diffuse calcification of the gallbladder (so-called porcelain gallbladder) is 12 to 21 percent. Most gallbladder cancers are well-to-moderately differentiated adenocarcinomas.
Some of these are papillary lesions that grow predominantly into the lumen of the
gallbladder. The main prognostic factor for gallbladder carcinoma is the clinical or pathologic stage There is a correlation between level of tumor invasion in the gallbladder wall and the presence of lymph node metastases. The gallbladder’s very thin wall and the discontinuous muscular layer are believed to facilitate tumor invasion and contribute to the advanced local and regional disease usually present at the time of diagnosis.
RISK FACTORS
Among other risk factors, a number of genetic, dietary factors, endo- and exobiotics, and chronic gallbladder infections, have been associated with the development of gallbladder cancer. However, the primary risk factor of gallbladder cancer as reported in all studies is gallstone disease.
CHOLELITHIASIS
Cholelithiasis is frequently associated with carcinoma gallbladder in up to 40%-100% patients and is the most common associated factor independent of age or sex. The risk of carcinoma gallbladder in patients with gallstones may be increased 4 to 7 times, and patients with gallstones >3cm in diameter have a much higher risk. Gallstones were found in 45% of our cases of carcinoma gallbladder. Carcinoma gallbladder is known to develop in patients with gallbladder preserving therapies for cholelithasis. However, the mode of carcinogenesis is not clear. It has been shown that chronic trauma and inflammation can induce epithelial dysplasia, carcinoma in situ and invasive cancer but a cause and effect relation has not been unequivocally proved.
CHRONIC CHOLECYSTITIS
Approximately 50% patients of carcinoma of the gallbladder have a history suggestive of chronic cholecystitis. It has been reported that carcinoma gallbladder may develop in 10% of patients with xanthogranulomatous cholecystitis.
PORCELAIN GALLBLADDER
There is a 20% risk of developing carcinoma gallbladder in patients with calcified or porcelain gallbladder making this an absolute indication for cholecystectomy.
GALLBLADDER POLYPS
Even though a definitive evidence similar to the adenoma carcinoma sequence in colonic cancer is lacking in carcinoma gallbladder, recent studies suggest that polyps greater than 10mm in diameter have a strong malignant potential. In one study by Kozuka et al, all the adenomas showing malignant change were larger than 12mm in diameter. If diagnosed in asymptomatic patients, cholecystectomy is recommended even in the absence of. However, for polyps <>CONGENITAL ANOMALIES
Recent studies have suggested that anomalous pancreaticobiliary duct junction (APBDJ) is a risk factor for carcinoma gallbladder. Gallbladder carcinoma occurred in 25% of the 65 patients with an anomalous union of the 2 duct systems as compared with 1.9% among 635 consecutive patients with a normal duct union. Anomalous duct union is seen in approximately 17% patients with carcinoma gall bladder as compared with less than 3% among patients with other hepatobiliary disorders. It is thought that this anomalous junction allows the free reflux of pancreatic juice into the gallbladder, the stasis of which damages the gallbladder mucosa and causes precancerous changes.
BILE AND BACTERIA
Primary bile acids are degraded to the secondary bile acids by anaerobic organisms in the large bowel, some of which are thought to be implicated in colonic carcinogenesis. Fox et al identified the presence of Helicobacter species in bile and gallbladder tissue from patients with cholelithiasis and cholecystitis but its relevance in carcinoma of the gallbladder is not yet established. A study from one centre has clearly shown significantly higher secondary bile acid in carcinoma of the gallbladder with positive culture. Among the different microbial agents salmonella typhi has been implicated frequently.
DIAGNOSIS
Early carcinoma gallbladder has no specific clinical presentation and preoperative diagnosis is rarely possible. Most of these patients are asymptomatic while a few present with clinical features suggestive of benign disease such as right upper abdominal pain interspersed with occasional attack of nausea and vomiting. In one study al, 48.2% of patients of carcinoma gallbladder had a preoperative diagnosis of symptomatic cholelithiasis. About 1% of patients operated for acute cholecystitis are found to have carcinoma gallbladder. Jaundice, presence of a lump and features of malignant cachexia such as anorexia and weight loss are a feature of extensive disease as is the presence of repeated attacks of vomiting which suggests gastric outlet obstruction due to tumour infiltration. The presence of a hard nodule in the liver and ascites indicates disseminated disease. In 15-20% of patients, carcinoma gallbladder is discovered either intraoperatively or postoperatively on histology, which in only 20% of the patients is the disease confined to gallbladder at diagnosis. The majority of the patients thus have locoregionally advanced or metastatic disease on first presentation.
TREATMENT
The treatment depends primarily upon the stage of the disease at presentation. The only potentially curative therapy is surgical resection. Unfortunately the overall resection rates at presentation range from 10%-30% only. Broadly management guidelines can be divided into three clinical groups.
1. Incidentally discovered carcinoma gallbladder during laparotomy or after cholecystectomy for benign disease.
2. Carcinoma gallbladder suspected or confirmed preoperatively on diagnostic workup.
3. Advanced carcinoma gallbladder diagnosed clinically or by preoperative investigations.
Carcinoma gallbladder is incidentally discovered during cholecystectomy for benign diseases in 12-36% of patients. If carcinoma gallbladder is discovered intraoperatively the surgeon has to decide whether curative surgery is possible after determining the extent of disease. If the disease is so extensive as to preclude curative resection then a biopsy along with the appropriate palliative procedure may be carried out. Sometimes the probability of carcinoma gallbladder becomes evident only after the gallbladder is opened up after removal hence it is important to examine the opened gallbladder carefully before closing the abdomen. More commonly, however it is only after histopathological examination of the diagnosis is made. Further treatment of such cases remain controversial. While most authors feel that simple cholecystectomy is adequate if the tumour has not invaded beyond the muscle layer reporting 5 year survival rates of nearly 100% The surgical management of carcinoma gallbladder diagnosed preoperatively depends upon the extent of the disease determined either by investigations or at laparotomy. Patients with disease confined to the gallbladder are treated by extended or radical cholecystectomy, but for disease extending beyond the gallbladder extended or radical cholecystectomy offers little, if any, survival advantage. Donohue et al reported a 5 year survival of 29% after extended cholcecystectomy in patients with transmural (T3, T4) tumour invasion and lymph node involvement as compared to no survivors after simple cholecystectomy in this group of patients. Matsumoto et al, Nakamura et al, Ogura et al and Ouchi et al advocate more extensive surgery such as excision of bile ducts, more extensive liver resections and even pancreaticoduodenectomy to further increase survival rates. Although some long term survivors have been reported, the morbidity and mortality of these procedures is high (48-54% and 15- 18% respectively) especially in patients with obstructive jaundice. Nakamura et al reported 54% 1 year survival, 23% 2 year survival and 15% 5 year survival rate for patients with TNM stage IV carcinoma gallbladder. The criteria for respectability can vary but presence of multiple peritoneal or liver metastases, distant metastases, extensive involvement of hepatoduodenal ligament, encasement or occlusion of major vessels and poor performance status are contraindications for surgical resection. Direct involvement of colon, duodenum or liver however, are not absolute contraindications for resectional surgery. In patients not fit for tumour resection, some form of palliative procedure such as a surgical bilioenteric bypass or endoscopic/percutaneous stenting in patients with obstructive jaundice may be done. Since the level of tumour obstruction is usually at the common hepatic duct or above, the round ligament approach to the segment III duct along with a biliary enteric anastamoses provides good palliation. In the presence of tumour invasion of the umbilical fissure of the liver, segment III bypass is not possible and recourse has to be taken for an alternative approach such as the Longmire procedure. Advances in endoscopic and radiologically guided percutaneous stenting have made operative bypass procedures in patients with unresectable cancer largely redundant. For patients with distal common bile duct obstruction an endoscopically placed stent provides good palliation whereas the percutaneous approach does the same for more proximal obstructions. These patients rarely live long enough to require stent replacement.
PROGNOSIS AND SURVIVAL
The stage at presentation is the most important prognostic determinant. Presently, the overall survival of carcinoma of the gallbladder is extremely discouraging. Hension et al, have shown 2 year survival is 45% for stage I, 15% for stage II, 4% for stage III and 2% for stage IV. Medical survival is 19, 7, 4 and 2 months for stage I, II, III and IV disease respectively. If the serosal layer is invaded the 5 year survival decreases to 91% if resection margins are negative on reexploration and to 43% with positive resection margins.
J Cancer Res Clin Oncol 1993;119(3):165-171; Gastroenterology 1998;115:937-946; Cancer 1992;70: 410-414; Am J Surg Pathol 1984; 8:323-333;Br J Surg 1990, 77: 363;Langenbecks Arch Surg 2000, 382: 501-508;Br J Surg 1994, 81: 1655-1657;Cancer 1995, 76: 1747-1756;World J Surg 2003, 27: 266-271
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