Prevention of Gallbladder Cancer

　　Improving the diagnosis and treatment of gallbladder cancer has been a challenge for surgeons since deStoll first described it in 1777. The incidence rate of primary carcinoma of gallbladder varies widely in different regions of the world, ranging from 1/100,000 to 27/100,000, and the incidence rate varies greatly between genders, with the incidence rate in women being 3-4 times higher than that in men. The peak age of incidence is around 60 years old.　　As the most common biliary tract malignant tumor, primary gallbladder cancer occupies the fifth place in the incidence of gastrointestinal malignant tumors. Gallbladder cancer often has no specific clinical symptoms in the early stage and is easily confused with benign gallbladder lesions such as gallbladder stones or cholecystitis, so the early diagnosis rate is low. Most of the gallbladder cancers that can be diagnosed clinically are in the middle and late stages, and many patients have lost the opportunity of surgery. Due to the high malignancy of gallbladder cancer, even if radical surgery can be performed, the 5-year survival rate of progressive gallbladder cancer after surgery is only 2-3%, so the overall prognosis is poor.　　How to improve the efficacy of gallbladder cancer is the direction of surgeons’ efforts, and prevention of etiology to reduce the incidence, regular screening of susceptible people, early diagnosis and early treatment are the most important. At present, the cause of gallbladder cancer is still unclear, but studies have found that benign diseases such as cholecystitis, gallbladder stones, gallbladder polyps and congenital abnormalities of pancreaticobiliary ducts are closely related to the occurrence of gallbladder cancer. Atypical hyperplasia of the gallbladder mucosa and gallbladder adenoma are currently recognized as precancerous lesions of the gallbladder. Therefore, proper understanding of benign gallbladder diseases, attaching importance to precancerous gallbladder lesions and grasping reasonable timing of surgery are the keys to reduce the incidence of gallbladder cancer, increase the early diagnosis rate and improve the prognosis of gallbladder cancer patients.　　In the 1930s, Graham found that 69%-100% of gallbladder cancer patients had gallbladder stones and 4.5%-14.0% of gallbladder stone patients had gallbladder cancer, suggesting that gallbladder stones are related to gallbladder cancer. Later, a large number of studies found that gallbladder cancer and gallbladder stones coexist, and many scholars therefore believe that gallbladder stones can induce cancer. In 1997, the incidence of gallbladder cancer with gallbladder stones ranged from 31% to 89% in 31 groups of 2300 gallbladder cancer patients nationwide. The incidence of gallbladder cancer in patients with gallbladder stones was about 7 times higher than that in those without stones.　　Over the past century, scholars at home and abroad have conducted many studies on the causes of gallbladder cancer caused by gallbladder stones. Based on the histopathological examination, it is common to see chronic inflammatory changes in the paracancerous tissues of gallbladder and precancerous lesions such as atypical hyperplasia or intestinal epithelial metaplasia in some epithelia. Some other scholars found that patients with gallbladder cancer combined with gallbladder stones have a history of long-term recurrent gallbladder inflammation, which causes gallbladder wall thickening, loss of normal elasticity, different degrees of destruction of the mucous membrane layer, cystic wall fibrosis and lamellar calcification, which can further develop into thickening and hardening of the whole gallbladder wall, forming porcelain gallbladder, and the mucous membrane of porcelain gallbladder can develop into cancer through atypical hyperplasia. The mucosa of the porcelain gallbladder evolves into cancer through atypical hyperplasia.　　Shi Jingsen et al. reported that the pathological patterns of 379 resected specimens of cholelithiasis and cholecystitis were studied: 79.68% had simple hyperplasia of the mucosa, 16.89% had atypical hyperplasia, 1.32% had carcinoma in situ, and 2.11% had invasive carcinoma. They found that simple hyperplasia of all types was present in the mucosa of cholelithiasis or cholecystitis, atypical hyperplasia and carcinoma on the background of simple hyperplasia, in situ carcinoma with all levels of atypical hyperplasia, and invasive carcinoma with both in situ carcinoma and severe atypia. The average age of patients with simple hyperplasia, atypical hyperplasia, carcinoma in situ and infiltrative carcinoma showed an increasing pattern. Thus, it is believed that the formation of gallbladder cancer is a series of changes through simple hyperplasia, atypical hyperplasia, carcinoma in situ, and finally infiltrating cancer. Similarly, Albores-Saavedra et al. reported that among 200 surgical specimens of cholelithiasis or cholecystitis, 83% had epithelial hyperplasia, 13.5% had atypical hyperplasia, and 3.5% had carcinoma in situ. They hypothesized that a series of mucosal cytopathological changes occur in cholelithiasis or cholecystitis: hyperplasia, atypical hyperplasia, and carcinoma in situ. They hypothesized that it takes about 5 to 10 years for atypical hyperplasia to develop into carcinoma in situ and further into invasive carcinoma.　　The size, number and nature of gallbladder stones are associated with their carcinogenicity. As the size and number of stones increase, the risk of gallbladder cancer increases. The composition and mutagenicity of gallstones remain inconclusive. Some reports suggest that 82% to 90% of the types of stones that coexist with gallbladder cancer are cholesterol stones and only 7% to 15% are bile pigment stones. Jiang Zhaoyan et al. reported that gallbladder stones in patients with gallbladder cancer tend to be multiple, larger and heavier in Shanghai. The average weight of stones in patients with gallbladder cancer was significantly higher than that in patients with cholelithiasis. Most scholars believe that the relationship between gallstones and gallbladder among the risk factors of gallbladder cancer is characterized by: stones >3 cm in diameter and gallbladder filled with stones.　　In recent years, the mechanism of bacterial action in the process of gallbladder cancer caused by gallbladder stones has received increasing attention. Gallbladder stones irritate the gallbladder mucosa leading to damage and affect its mechanical contraction and emptying function. Repeated chronic inflammation of the gallbladder with prolonged microbial infection, on the basis of which mucosal metaplasia of the gallbladder ensues, through the pathway of atypical hyperplasia, carcinoma in situ and finally developing into invasive carcinoma, in which infection is an important risk factor. The mechanism is that biliary obstruction and infection can convert bile acids into more active carcinogenic substances, such as deoxycholic acid and cholelithiatic acid. Pills made of bile acids, deoxycholic acid and methylcholanthrene implanted into the gallbladder of cats can induce gallbladder cancer. S. typhi and Helicobacter gallinarum were found to be the main microorganisms that induce gallbladder cancer in gallbladder stones through the pathological mechanism of bacterial infection.　　Mirizzi’s syndrome is a rare complication of gallbladder stones, which refers to narrowing and obstruction of the common hepatic duct due to stone impaction in the gallbladder neck or cystic duct or its secondary inflammation, with recurrent biliary inflammation and obstruction, accounting for 0.7-1.4% of all cholecystectomy patients, The incidence of gallbladder cancer in Mirizzi’s syndrome was 27.8%, while the incidence of gallbladder cancer in the control group of cholecystectomy specimens was only 2%, indicating that Mirizzi’s syndrome is closely related to gallbladder cancer. The incidence of gallbladder cancer in resected gallbladder specimens in the Mirizzi syndrome group was 17.6% compared with 1.48% in normal gallbladder specimens in the control group in China. These data suggest that patients with Mirizzi syndrome have a significantly increased risk of gallbladder cancer, probably because Mirizzi syndrome includes all the pathological processes similar to those that cause gallbladder mucosal damage due to gallbladder stones leading to gallbladder cancer, including persistent damage to the gallbladder mucosa, recurrent episodes of cholecystitis leading to ulceration and fibrosis of the gallbladder wall, causing simple to atypical epithelial hyperplasia of the gallbladder mucosa. At the same time, the retrograde bacterial infection in the intestine leads to changes in the chemical composition of bile such as bile acids and chemical carcinogens. This shows that Mirizzi syndrome is a high risk factor in the development of gallbladder cancer, which cannot be ignored.　　Family history of gallbladder stone disease was also found to be correlated with gallbladder cancer. Family history of gallstone disease significantly increased the risk of gallbladder cancer, with women having a significantly higher risk of gallbladder cancer than men in the family, which is consistent with the increased risk of gallstone disease in women, and these studies further support gallbladder stones as a factor in the development of gallbladder cancer. ATP binding cassette (ABC) G5 and G8, which are cholesterol transport proteins in the lateral membranes of hepatic bile ducts and promote biliary cholesterol secretion, were found to be susceptible to the development of gallstone disease. In a case-control study of Shanghai gallstone patients and gallbladder cancer patients, Xu et al. found that CG genotype carriers of the ABCG8 gene rs11887534 (D19H) polymorphism had a higher risk of gallstone disease and gallbladder cancer. The same findings exist in foreign population studies. The common susceptibility genes for gallbladder cancer and gallbladder stones suggest a correlation between gallbladder stones and gallbladder cancer development. Other studies have found that carriers of some genetic polymorphisms related to inflammation, hormones, lipid metabolism, insulin sensitivity, etc., will increase the risk of gallstone disease and also increase the risk of gallbladder cancer.　　In conclusion, both clinical reports and experimental studies show that gallbladder stones are prone to gallbladder mucosal hyperplasia, followed by chemosis, and eventually have a high potential for carcinogenesis, which is the most common high-risk factor for gallbladder cancer.　　Piehler et al. found that 40% to 50% of gallbladder cancer patients had a history of chronic cholecystitis, and thus considered cholecystitis as a very important cause of gallbladder cancer. Bacterial infection is not a common cause of cholecystitis, but many gallbladder infections are associated with gallbladder stones, thus chronic cholecystitis with stones is also a high risk factor for gallbladder cancer. The wall of chronic cholecystitis without stones may thicken or thin due to repeated inflammation, gradually lose its normal elasticity, develop into fibrosis and lamellar calcification, and the mucous membrane layer may be damaged and proliferated to different degrees, which may further develop into thickening and hardening of the whole gallbladder wall, forming porcelain-like gallbladder. The porcelain-like gallbladder mucosa gradually evolves into cancer through atypical hyperplasia and has a high risk of carcinogenesis.　　Yellow granulomatous cholecystitis is a rare and specific type of inflammatory gallbladder disease characterized by the formation of yellow patches or waxy granulomas within the gallbladder wall. The pathogenesis of yellow granulomatous cholecystitis is due to ulceration or rupture of the mucosa of the Rokitansky-Aschof sinus in the wall of the gallbladder due to a combination of inflammation and obstruction, which leads to infiltration and proliferation of mononuclear macrophages in the wall of the gallbladder. Lipids and cholesterol in the bile are phagocytosed by mononuclear macrophages and form foam cells and multinucleated giant cells, which accumulate and form granulomatous lesions. Yellow granulomatous cholecystitis and gallbladder cancer are both developed from cholecystitis, and they are closely related and often difficult to distinguish clinically.　　Polypoid lesion of gallbladder and gallbladder cancer Polypoid lesion of gallbladder (PLG) is not a single disease, but refers to a type of lesion in which the mucous membrane of gallbladder is restrictedly elevated or protrudes into the lumen of gallbladder, which is often detected by ultrasound. In the early stage of gallbladder cancer, there may be polyp-like manifestation in the imaging diagnosis, but it should not be classified as gallbladder polyp-like lesion in the pathology. Benign polypoid lesions can be divided into epithelioid tumors, mainly adenomas; mesenchymal tumors, including fibromas, lipomas, and hemangiomas; or pseudotumors, including cholesterol polyps, inflammatory polyps, and adenomyosis glands of the gallbladder. This chapter focuses on the relationship between benign gallbladder polyps and gallbladder cancer.　　Neoplastic polyp lesions of the gallbladder are predominantly adenomatous. Kozuka et al. reviewed the histologic data of 1605 patients with gallbladder disease and found 7 cases of adenoma with carcinoma and 79 cases of invasive carcinoma. they concluded that an adenomatous component was present within all in situ carcinomas and 19% of invasive carcinomas, further confirming the transformation of adenocarcinoma from adenoma, supporting evidence that (1) histologic migration of adenoma to adenocarcinoma exists and (2) adenoma (2) adenoma is present in all malignant specimens; (3) adenoma is common in gallbladder cancer; (4) adenoma enlargement is accompanied by an increased incidence of carcinoma; and (5) the average age of patients increases by adenoma, carcinoma in situ, and invasive carcinoma. Some basic studies have also revealed the possibility of adenoma malignancy, and Lenriot et al. found that indicators of cellular heterogeneity and DNA content increased gradually and differentially from normal gallbladder epithelium – simple adenoma – adenoma malignancy – primary gallbladder adenocarcinoma. As the degree of adenoma hyperplasia increases, the proportion of DNA heteroploidy increases and the cells have an increased ability to proliferate and divide, thus having a greater propensity for malignancy. Experimental studies on aggrecan receptors, sex hormone receptors, C-erbB-2 protein expression, and carcinoembryonic antigen in gallbladder polyps have also revealed a close correlation with tumors. There is a consensus that adenomatous polyps are potential precancerous lesions of the gallbladder and are closely related to the development of gallbladder cancer.　　Among the non-neoplastic polyps, cholesterol polyps are the most common, followed by inflammatory polyps, adenomatous hyperplasia and adenomyoma. Cholesterol polyps are characterized by multiple small polyps, whereas neoplastic polyps tend to be single lesions. Cholesterol polyps are pathologically characterized by brittle and thin tissues, easily separated from the mucosa, without intestinal metaplasia or atypical hyperplasia, and without other stromal components, even with minimal inflammation. Inflammatory polyps of the gallbladder are also more common and are not true polyps, but appear as single or multiple broad-based nodules due to inflammatory stimulation. They are composed of capillaries, fibroblasts and chronic inflammatory cells, and there is significant inflammation in the gallbladder wall surrounding the polyps.　　The hyperplasia is characterized by hyperplasia of the gallbladder glands and smooth muscles, which protrudes into the muscular layer or even into the subplasma membrane, called Rokitansky-Aschoff sinus, and is a non-inflammatory, non-neoplastic disorder. The mucosal hyperplasia of the gallbladder increases in size, the muscle hyperplasia thickens the wall of the gallbladder, and the nerve fibers in the wall of the gallbladder proliferate abnormally, causing the accumulation of bile in the Rokitansky-Aschoff sinus and the formation of stones secondary to inflammation. According to the distribution of the lesions in the gallbladder wall, they are classified into diffuse, segmental and limited types. The diagnosis of this disease is not difficult because of the characteristic features of ultrasound, CT and MRI imaging. In the past, it was thought that adenomyosis was not malignant, but since Nakafuli reported a case of carcinoma in adenomyosis of gallbladder in 1981, malignant changes have been reported in recent years, and now most scholars believe that adenomyosis of gallbladder is a precancerous lesion of gallbladder.　　4.Anomalous junction of the pancreaticobiliary duct (AJPBD) refers to the anatomical convergence of the common channel of the pancreaticobiliary duct outside the wall of the duodenum, resulting in the common channel being too long, so that the sphincter of Oddi cannot control the whole joint, and the bile and pancreatic juices flow backwards to each other, causing the bile duct and pancreatic juice to flow backwards. The common channel is too long, so that the sphincter of Oddi can not control the whole joint, and the bile and pancreatic juices flow backward to each other, causing a series of biliary and pancreatic diseases. Clinically, AJPBD is often divided into two categories: with bile duct dilatation and without bile duct dilatation, of which about 80% are bile duct dilatation, which is easy to detect because of the obvious symptoms and signs. There are various clinical types of AJPBD, the simpler one is based on the confluence mode, the pancreatic duct merging into the bile duct is called P-B type; the bile duct merging into the pancreatic duct is called B-P type; and other complex types.　　AJPBD was first proposed by Babbit in 1969, and with the development of anatomy and imaging, it was found to be closely related to gallbladder cancer. 65 cases of pancreaticobiliary duct coarctation abnormalities were reported by Kimura, and 16 cases were combined with gallbladder cancer, including 11 cases of gallbladder cancer with pancreaticobiliary duct coarctation abnormalities without dilatation of the common bile duct. Nagai et al. found that the incidence of gallbladder cancer in pancreaticobiliary duct coarctation without cystic dilatation was higher than that of bile duct cancer. Based on epidemiological studies of a large number of patients with AJPBD, many scholars have suggested that AJPBD is an important risk factor for the development of gallbladder cancer.　　The main mechanisms of AJPBD causing gallbladder and bile duct cancer are: (1) the theory of pancreatic reflux; AJPBD patients have pancreatic reflux into bile duct due to the inability of Oddi sphincter to control the whole sympathetic part, under the action of bile, pancreatic digestive enzymes are activated, and the activated digestive enzymes repeatedly stimulate and damage the mucosa of bile duct, causing chronic inflammation and tissue chemosis and hyperplasia of the mucosa, and eventually cancer occurs. (2) The theory of carcinogenesis by mutagenic substances in bile. Under the action of regurgitated pancreatic juice or bile, phospholipase A2 in pancreatic juice can hydrolyze lecithin in bile to produce lysolecithin (LysoPC) and fatty acids. LysoPC has a strong cytotoxic effect on the bile duct epithelium, which repeatedly damages and eventually causes bile duct mucosal damage and carcinogenesis. (3) Bile acid carcinogenesis theory: AJPBD patients have an increased concentration of secondary and free bile acids in bile, which is potentially carcinogenic, and this pro-carcinogenic activity is achieved through prostaglandin E2 and cyclooxygenase-2 pathways. In terms of molecular biology, great progress has been made in the study of the mechanism of biliary tract carcinogenesis by AJPBD. Ichikawa et al. found that in patients with AJPBD gallbladder cancer, non-cancerous gallbladder mucosal tissue showed altered bcl-2 expression and telomerase activity, but no abnormalities in p53, Ki-67 or k-ras genes. Tanno et al. found that 63% of patients with AJPBD had hyperplasia of the gallbladder mucosa epithelium, and Ki-67 expression was upregulated in the hyperplastic gallbladder mucosa with K-ras mutations. The COX-2 inhibitor meloxifene was found to inhibit gallbladder carcinogenesis in animal models of AJPBD.　　Other risk factors for gallbladder cancer Gallbladder cancer is a common malignant tumor of the biliary system, and epidemiological surveys show that the incidence varies greatly among different regions and different races of people of different sexes. The incidence is higher in the northeast of China than in the south of Yangtze River. The incidence of gallbladder cancer is higher in rural areas than in urban areas, and the incidence of gallbladder cancer is higher in those with combined gallbladder stones; in addition, obesity or Salmonella infection are also risk factors for gallbladder cancer.　　Recent molecular biology studies have found that some genes or biomolecules, such as c-myc, Bcl-2, p53, p16, survivin, etc., are related to the occurrence, development, or metastasis of gallbladder cancer, suggesting that genetic factors may play a role in the development of gallbladder cancer. .　　Second, early surgery for benign gallbladder diseases Primary gallbladder cancer is a malignant tumor with high malignancy and poor prognosis. Even if radical surgery can be performed, the postoperative effect of progressive gallbladder cancer is poor; therefore, removing the cause of gallbladder cancer, early detection and early treatment are the keys to improve the curative effect. For the high-risk groups prone to gallbladder cancer, actively dealing with benign gallbladder disorders, removing the gallbladder and removing the sites of gallbladder cancer development may be an important way to reduce the incidence of gallbladder cancer and improve the efficacy of gallbladder cancer.　　 (5) for asymptomatic gallbladder stones with a diameter greater than 2.0 cm or multiple stones, filled stones. The above-mentioned as indications for gallbladder stone surgery can solve the stone disease and remove the high-risk factors for gallbladder cancer. We believe that the surgical indications should be appropriately relaxed for patients with some other high-risk factors, such as women over 50 years of age, or in high-incidence areas, with a family history of hereditary gallbladder stones or gallbladder cancer, and in high-risk occupations. For patients with very high risk factors such as Mirizzi syndrome, gallbladder wall thickening or atrophy, yellow granulomatous cholecystitis, and porcelain-like gallbladder, the gallbladder specimen should be examined by rapid frozen section when undergoing surgery to avoid missing the diagnosis of gallbladder cancer that has already occurred and to achieve timely management of unexpected gallbladder cancer.　　Indications for surgery of gallbladder polyp-like lesions. Since inflammatory gallbladder polyps and cholesterol polyps have no tendency to become cancerous, only some other types of polyps are early gallbladder cancer or precancerous lesions, which require the identification of lesions prone to gallbladder cancer from gallbladder polyp-like lesions so that they can be removed as early as possible. At the same time, it is important to minimize the number of gallbladders that are not predisposed to cancer. Most scholars consider the following as indications for surgery of gallbladder polyp-like lesions: (1) solitary lesions; patients older than 50 years; (2) polyps >10 mm in diameter or broad-based polyps; (3) combined with other gallbladder diseases, such as stones, cholecystitis or gallbladder wall thickening and other risk factors for gallbladder cancer; (4) gallbladder adenomyosis combined with gallbladder stones or suspected malignant changes. Gallbladder polyp surgery mode surgery is simple cholecystectomy, the purpose is to remove gallbladder lesions while preventing and treating gallbladder cancer, in the surgery should be combined with frozen pathological section examination to prevent missing early gallbladder cancer, for early gallbladder cancer, should be handled according to the principle s of gallbladder cancer surgery. For early-stage gallbladder cancer, it should be treated according to the principles of gallbladder cancer surgery. For PLG <10mm in diameter, we cannot let down our vigilance and must follow up regularly. For the treatment of PLG, we emphasize that we should not blindly expand the indications for surgery in order to prevent gallbladder cancer, but also to prevent the occurrence of cancer and miss the opportunity of surgery.　　The incidence of gallbladder cancer with abnormal pancreaticobiliary duct cohesion is much higher than that of normal subjects. Therefore, if preoperative MRCP, ERCP, percutaneous transhepatic cholangiography (PTC) or intraoperative cholangiography reveals abnormal pancreaticobiliary duct cohesion, the gallbladder should be carefully examined while other biliary and pancreatic diseases are treated during surgery. For patients with cystic dilatation of the common bile duct due to abnormal pancreaticobiliary flow, the gallbladder should be removed at the same time when reconstructive surgery of the biliary system is performed.　　At present, the surgical treatment of gallbladder cancer is not effective, so removing the cause and preventing the occurrence of gallbladder cancer is the key. In terms of removing the causes of gallbladder cancer, correctly understanding the relationship between benign gallbladder diseases and gallbladder cancer, attaching importance to and dealing with high-risk factors, actively dealing with precancerous gallbladder lesions, grasping reasonable surgical timing to deal with benign gallbladder lesions, removing the gallbladder, and removing the site of gallbladder cancer development are the most important to reduce the incidence of gallbladder cancer and improve the prognosis of gallbladder cancer patients. At the same time, we emphasize that the indications for cholecystectomy surgery should never be blindly expanded for the purpose of gallbladder cancer prevention